Carriers for storage and transport of biological samples

ABSTRACT

Disclosed herein are devices, apparatus, systems, methods and kits for collecting and storing a fluid sample from a subject. A device for collecting the fluid sample can include a housing comprising a recess having an opening, a vacuum chamber in the housing and in fluidic communication with the recess, and one or more piercing elements that are extendable through the opening to penetrate skin of the subject. The vacuum chamber can be configured for having a vacuum that draws the skin into the recess. The recess can be configured having a size or shape that enables an increased volume of the fluid sample to be accumulated in the skin drawn into the recess.

CROSS-REFERENCE

This application is a continuation application of U.S. Ser. No.16/104,846, filed on Aug. 17, 2018, which is a continuation ofInternational Application Serial No. PCT/US2018/013223, filed on Jan.10, 2018, which claims the benefit of U.S. Provisional Application Ser.No. 62/468,906, filed on Mar. 8, 2017 and U.S. Provisional ApplicationSer. No. 62/444,764, filed on Jan. 10, 2017, all of which areincorporated herein by reference in their entirety.

BACKGROUND

Body fluid collection, for example collection of blood samples forperforming diagnostic tests, can be used to assess and inform the healthof individuals. Early detection and reliable diagnosis can play acentral role in making effective therapeutic decisions for treatment ofdiseases or managing certain physiological conditions. Detection caninvolve identification of disease-specific biomarkers in human bodyfluids that can indicate irregularities in cellular regulatoryfunctions, pathological responses, or intervention to therapeutic drugs.

Many individuals, however, may not relish the process of having blooddrawn from their bodies, possibly due to association with pain, cuts,bleeding, sharp objects, sight of blood, fear of infections, etc.Typically, venous blood collection of a subject is performed at externalfacilities such as hospitals, skilled nursing facilities, and outpatientenvironments such as primary care physician (PCP) & specialty hospitalclinics, surgery centers, occupational health clinics, or physicianoffices. The blood collection process can be tedious and time consumingfor individuals who have to visit those facilities for blood draw, andfor healthcare personnel who can have to attend to multiple patientencounters within a single day.

Thus, a need exists for improved devices and methods that enable bloodcollection to be performed easily and conveniently by users, and thatcan decrease users' reliance on traditional healthcare facilities forblood draw.

SUMMARY

The present disclosure addresses at least the above needs. Variousembodiments of the present disclosure address the demand for devices andmethods, that enable individuals to easily, conveniently, and reliablycollect and store blood samples outside of traditional healthcarefacilities, for example in their own homes, in remote locations, whiletraveling, etc. Individuals who have minimal to no medical training canuse the disclosed devices and methods to efficiently collect and storeblood on their own or with the help of others, without the need fortrained healthcare personnel. The embodiments described herein canobviate the need for individuals to schedule, or make special orfrequent trips to healthcare facilities for blood sample collection,which helps to free up the individuals' time and reduce patient load onhealthcare resources. Nonetheless, it should be appreciated that thedisclosed devices and methods are also suitable for use by healthcare ornon-healthcare personnel in a variety of environments or applications,for example in personalized point-of-care (POC), Emergency MedicalServices (EMS), ambulatory care, hospitals, clinics, emergency rooms,patient examination rooms, acute care patient rooms, field environments,nurse's offices in educational settings, occupational health clinics,surgery or operation rooms, etc.

Blood samples collected using the devices and methods described hereincan be analyzed to determine a person's physiological state, fordetecting diseases and also for monitoring the health conditions of theuser. In some instances, individuals can rapidly evaluate theirphysiological status since blood samples can be quickly collected usingthe devices and methods described herein, and either (1) analyzed on thespot using for example immunoassays or (2) shipped promptly to a testingfacility. The reduced lead-time for blood collection, analysis andquantification can be beneficial to many users, especially users whohave certain physiological conditions/diseases that require constant andfrequent blood sample collection/monitoring. Taking diabetes as anexample, hemoglobin A1c (HbA1c) can make up 60% of all glycohemoglobinsand can be used for monitoring glycemic control. The amount of HbA1c, asa percentage of total hemoglobin, can reflect the average blood glucoseconcentration in a patient's blood over the preceding 120 days.Generally it is recommended that diabetic patients test their HbA1clevels every three to six months. The glycemic recommendation fornon-pregnant adults with diabetes can be <7.0%, while HbA1c levelsof >8% can indicate that medical action can be required to controldiabetic complications, including cognitive impairment and hypoglycemicvulnerability.

The various embodiments described herein are capable of drawing blood atincreased flowrates and higher sample volumes beginning from time ofskin incision, compared to traditional non-venous blood collectiondevices and method. The disclosed devices and methods can be used tocollect blood samples of predefined volumes, for example through the useof custom matrices for sample collection, and absorbent pads for holdingand metering out excess blood. Additionally, the blood collectiondevices and methods described herein are minimally invasive and permitlower levels of pain (or perception of pain) in a subject, which canhelp to improve the overall blood collection experience for the subject.

In some aspects, a handheld user-activable device or method disclosedherein can be configured or capable of collecting at least 150 uL ofblood from a subject in less than 3 minutes beginning from time ofincision or penetration of a skin portion of the subject.

In some aspects, a device for collecting fluid sample from a subject isprovided. The device can comprise a recess and a pre-evacuated vacuumchamber located within the device. The recess can be configured tomaintain contact with at least 5.0 cm² of a skin surface area of thesubject under vacuum pressure, prior to and as the fluid sample is beingcollected from the skin of the subject.

In some aspects, a device for collecting fluid sample from a subject cancomprise: a housing comprising a recess having an opening; a vacuumchamber in the housing in fluidic communication with the recess; and oneor more piercing elements that are extendable through the opening topenetrate skin of the subject. The vacuum chamber can be configured forhaving a vacuum that draws the skin into the recess, and the recess canbe configured having a size or shape that enables an increased volume ofthe fluid sample to be accumulated in the skin drawn into the recess.

In some aspects, a method for collecting a fluid sample from a subjectcan comprise: providing a device having a housing, said housingconfigured to support a vacuum chamber and a piercing module, thehousing comprising a recess having an opening; placing the recess of thehousing adjacent to skin of the subject; activating the vacuum in thevacuum chamber to draw the skin into the recess; accumulating anincreased volume of the fluid sample in the skin drawn into the recess,wherein the recess is configured having a size or shape that enables theincreased volume of the fluid sample to be accumulated; extending one ormore piercing elements through the opening to penetrate the skin; andmaintaining the device adjacent to the skin for a sufficient amount oftime to draw the fluid sample into the device.

In some embodiments, the fluid sample can comprise blood from thesubject. The recess can serve as a suction cavity for drawing the skinand increasing capillary pressure differential. The increased volume ofthe fluid sample can depend on a volume and/or surface area of the skinthat is drawn into the recess. In some cases, the volume of the skinenclosed by the recess can range from about 0.4 cm³ to about 4.0 cm³.The surface area of the skin in contact with the recess can range fromabout 3.2 cm² to about 7.2 cm². The increased volume of the fluid samplecan depend on a pressure of the vacuum in the vacuum chamber. Thepressure of the vacuum in the vacuum chamber can range from about −4psig to about −15 psig. The increased volume of the fluid sample in theskin drawn into the recess can be at least about 50 μL prior to thepenetration of the skin. In some cases, the increased volume of thefluid sample in the skin drawn into the recess, an increased capillarypressure, and with aid of the vacuum, can permit the fluid sample to bedrawn from the skin and collected at an average flowrate of at least 30μL/min. In some cases, the fluid sample can be collected at an averageflowrate of at least 100 μL/min. In some cases, the fluid sample can becollected at an average flowrate of at least 150 μL/min. In some cases,the average flowrate can be sustained at least until about 150-300 μL ofthe fluid sample has been collected. The size and/or shape of the recesscan be configured to permit the skin to substantially conform to therecess. A gap between the skin and the recess can be negligible when theskin is drawn into the recess. A surface of the recess can besubstantially in contact with the skin drawn into the recess. In somecases, a size of the recess can be at least two times a size of theopening within the recess. In some cases, the size of the opening withinthe recess can range from about 1.5 mm to about 6 mm, and the size ofthe recess at its outermost periphery can range from about 10 mm toabout 60 mm. A surface area of the recess can be substantially greaterthan an area of the opening. In some cases, the surface area of therecess can be at least ten times the area of the opening. In some cases,the surface area of the recess can range from about 75 mm² to about 2900mm², and the area of the opening can range from about 1.5 mm² to about30 mm². In some cases, an area of the skin directly under the openingcan be at least 1.5 times smaller than a total area of the skin drawninto the recess. In some cases, the area of the skin directly under theopening can be at least 5 times smaller than the total area of the skindrawn into the recess.

In some embodiments, the recess can comprise a concave cavity. In somecases, the concave cavity can have a volume ranging from about 1.0 cm³to about 5.0 cm³. The recess can be in the shape of a spherical cap. Insome cases, a base diameter of the spherical cap can range from about 10mm to about 60 mm, and a height of the spherical cap can range fromabout 3 mm to about 30 mm. The spherical cap can be a hemisphere. Theopening can be at an apex of the spherical-capped recess. In someembodiments, the recess can comprise one or more fillets configured toimprove vacuum suction to the skin and reduce vacuum leak. The one ormore fillets can extend continuously along a periphery of the recess.The one or more fillets of the recess can be configured to be in contactwith the skin when the skin is drawn into the recess.

In some embodiments, a vacuum pressure of at least about −1 psig can beprovided in order to draw the skin into and completely fill the recess.In some cases, the skin can be drawn into the recess by the vacuum andcan completely fill the recess in less than 1 second. In some cases, theskin can be drawn into the recess by the vacuum and can completely fillthe recess in no more than 5 seconds.

In some embodiments, (1) the size or shape of the recess or (2) apressure of the vacuum can be configured to achieve a minimum capillarypressure in the skin drawn into the recess. In some cases, (1) the sizeor shape of the recess or (2) a pressure of the vacuum can be configuredto achieve a minimum tension in the skin drawn into the recess. Thedevice can be supported and held in place on the skin of the subjectwith the aid of an adhesive. The device can be supported and held inplace on the skin of the subject with the aid of the vacuum. The devicecan be supported and held in place on the skin of the subject primarilywith the aid of the vacuum. The device can be configured for use on anupper portion of the subject's arm. The device can be configured toremain in its position on the subject's arm independent of any movementor changes in orientation of the subject's arm.

In some embodiments, the device can be capable of collecting 250 uL offluid sample from the subject in less than 1 minute 45 seconds. In somecases, the device can be capable of collecting at least 175 uL to 300 uLof fluid sample from the subject in less than 3 minutes. In some cases,the device can be capable of collecting at least 200 μL of fluid samplefrom the subject in less than 5 minutes. The device can be configured tocollect the fluid sample at a rate that is dependent on the size orshape of the recess and/or vacuum pressure. The recess can be configuredhaving a size and shape that enables an increased volume of the fluidsample to be accumulated in the skin drawn into the recess. The recesscan be configured having a size and shape that enables the increasedvolume of the fluid sample to be accumulated. In some cases, (1) thesize and shape of the recess and (2) a pressure of the vacuum can beconfigured to achieve a minimum capillary pressure in the skin drawninto the recess. In some cases, (1) the size and shape of the recess and(2) a pressure of the vacuum can be configured to achieve a minimumtension in the skin drawn into the recess. The device can be configuredto collect the fluid sample at a rate that is dependent on the size andshape of the recess.

In some other aspects, a device for collecting a fluid sample from asubject is provided. The device can comprise: a housing comprising apiercing activator configured to activate one or more skin piercingelements, and a vacuum activator separate from the piercing activatorand configured to activate an evacuated vacuum chamber prior to theactivation of the one or more piercing elements by the piercingactivator.

In some aspects, a method for collecting a fluid sample from a subjectcan comprise: placing a device packaged with an evacuated vacuum chamberand one or more piercing elements on skin area of the subject;activating the evacuated vacuum chamber to effectuate vacuum pressure onthe skin area; piercing the skin area after vacuum activation; andmaintaining the vacuum pressure during and after penetrating the skinarea of the subject, in order to draw the fluid sample from the skininto device.

In some embodiments, the piercing activator and the vacuum activator canbe two separate components. The vacuum activator can comprise a firstinput interface on the housing, and the piercing activator can comprisea second input interface on the housing. In some cases, at least one ofthe first input interface or the second input interface can comprise abutton. In some alternative cases, the vacuum activator can comprise afirst input interface and the piercing activator can comprise a secondinput interface, and at least one of the first input interface or thesecond input interface can be remote from the housing.

In some embodiments, the piercing activator can be configured toactivate the one or more piercing elements after the skin is drawn intothe recess. The piercing activator can be configured to activate the oneor more piercing elements after the skin is drawn into the recess by thevacuum for a predetermined length of time. In some cases, thepredetermined length of time can range from about 1 second to about 60seconds. In some embodiments, the housing can comprise the pre-evacuatedvacuum chamber, and the vacuum activator can be configured to activatethe vacuum in the pre-evacuated vacuum chamber. In some cases, thepiercing activator can be configured to activate the one or morepiercing elements only after the vacuum has been activated. In somecases, the piercing activator can be locked and incapable of activatingthe one or more piercing elements prior to activation of the vacuum. Thepiercing activator can comprise a locking mechanism coupled to thevacuum activator. The locking mechanism can be configured such that thepiercing activator is initially in a locked state. The vacuum activatorcan serve as a key for unlocking the piercing activator, and thepiercing activator can be simultaneously unlocked when the vacuumactivator is activated. The vacuum activator can be configured toactivate the vacuum by establishing fluidic communication to thepre-evacuated vacuum chamber. For example, the vacuum activator can beconfigured to pierce a foil seal or open a valve to establish thefluidic communication to the pre-evacuated vacuum chamber.

In some embodiments, the vacuum activator can be located on the housingsuch that the vacuum activator is configured to be pressed in a firstdirection, and the piercing activator can be located on the housing suchthat the piercing activator is configured to be pressed in a seconddirection. In some cases, the first direction and the second directioncan be substantially the same. Alternatively, the first direction andthe second direction can be substantially different. In some cases, thefirst direction and the second direction can be substantially parallelto each other. In some cases, at least one of the first direction or thesecond direction does not extend toward the skin of the subject. Forexample, the second direction does not extend toward the skin of thesubject. In some cases, at least one of the first direction or thesecond direction can extend substantially parallel to the skin of thesubject. In some cases, the first direction and the second direction canboth extend substantially parallel to the skin of the subject. In somecases, at least one of the first direction or the second direction canextend in a direction of gravitational force. In some cases, the firstdirection and the second direction can both extend in the direction ofgravitational force. In some embodiments, the piercing activator and thevacuum activator can be located on a same side of the housing, and canbe ergonomically accessible by the subject when the device is mountedonto an arm of the subject. For example, the piercing activator can belocated on a cover of the housing, and the vacuum activator can belocated on a base of the housing where the vacuum chamber is located.Alternatively, the piercing activator and the vacuum activator can belocated on different sides of the housing, and can be ergonomicallyaccessible by the subject when the device is mounted onto an arm of thesubject.

In some further aspects, a method for collecting a fluid sample from asubject is provided. The method can comprise: with aid of a fluidacquisition device: piercing skin of the subject and delivering thefluid sample from the subject to a matrix disposed within a depositionchamber of the fluid acquisition device, wherein the delivery of thefluid sample is assisted or enhanced using (1) gravitational force, (2)vacuum force, (3) a pressure difference between capillary pressure andinternal pressure of the device, and (4) wicking behavior of the fluidsample along the matrix.

In some aspects, a device for collecting a fluid sample from skin of asubject and delivering it to a deposition chamber is provided, whereinfluid flow from the skin to a matrix in the deposition chamber can bepreferably enhanced by (1) gravitational force, (2) vacuum force, (3) apressure differential between capillary pressure and internal pressureof the device, and (4) wicking behavior of the fluid sample along thematrix.

In some embodiments, the device can comprise an enclosure for holdingone or more piercing elements, and the enclosure can be in fluidiccommunication with the deposition chamber. The deposition chamber andthe enclosure can be initially at ambient pressure, prior to activationof a vacuum from a pre-evacuated vacuum chamber located onboard thedevice. In some cases, the deposition chamber, the vacuum chamber, andthe enclosure can be configured to equalize to an internal pressure thatis less than the ambient pressure after the vacuum has been activated.The internal pressure can be higher than the initial evacuated vacuumpressure of the vacuum chamber. In some cases, the internal pressure canbe about −5.5 psig, and the sealed vacuum pressure can be about −12psig. The internal pressure can be configured to draw the skin into arecess of the housing. The internal pressure can be configured to drawblood from capillary beds to the skin that is being drawn into therecess. A pressure differential can be created between capillarypressure and the internal pressure when the skin is penetrated by one ormore piercing elements of the device. The internal pressure can increaseas the fluid sample is drawn from the skin towards the depositionchamber and the enclosure. In some cases, the internal pressure in theenclosure can increase more rapidly compared to a collective internalpressure of the deposition chamber and the vacuum chamber. The internalpressure in the enclosure can increase substantially more than thecollective internal pressure of the deposition chamber and the vacuumchamber. The substantially increased internal pressure of the enclosurecan inhibit the flow of the fluid sample into the enclosure. Thesubstantially increased internal pressure of the enclosure can result inpreferential flow of the fluid sample towards the deposition chamberinstead of towards the enclosure. The substantially increased internalpressure of the enclosure can cause the flow of the fluid sample intothe enclosure to slow or stop, while the fluid sample can continue toflow towards the deposition chamber under the influence of the pressuredifferential. In some cases, (1) a volume of the enclosure and (2) acollective volume of the deposition chamber and the vacuum chamber, canbe configured such that minimal amounts of the fluid sample flowstowards and into the enclosure. In some cases, a ratio of the volume ofthe enclosure to the collective volume of the deposition chamber and thevacuum chamber can range from about 1:5 to about 1:15. In some cases,the one or more piercing elements can be configured to penetrate theskin to generate cuts, and the pressure differential can enable deepercuts and the cuts to be held open under tension. The pressuredifferential can be configured to increase the size of the cuts toenable a higher flowrate and volume of the fluid sample to be collectedfrom the skin.

In some further aspects, a device for penetrating skin of a subject isprovided. The device can comprise: one or more piercing elementssupported by a piercing holder movable by two or more spring elements; adeployment spring positioned to deploy the one or more piercing elementsthrough an opening in the device; and a retraction spring positioned toretract the one or more piercing elements back into the device, whereina length of the one or more piercing elements is less than about 20 mm,and the depth of penetration of the one or more piercing elements isabout 2 mm. In some cases, the length of the one or more piercingelements is about 12.7 mm.

In some aspects, a method for penetrating skin of a subject can compriseproviding the aforementioned device; drawing the skin of the subjectinto a recess of the device; activating the deployment spring anddeploying the one or more piercing elements through the opening in thedevice; penetrating the skin of the subject using the one or morepiercing elements; and using the retraction spring to retract the one ormore spring elements back into the device.

In some embodiments, two or more piercing elements can be supported by aholder in a random configuration. In some cases, the two or morepiercing elements can have random orientations relative to each other.The two or more piercing elements can comprise beveled edges that arerandomly oriented relative to each other. The beveled edges of the twoor more piercing elements can be non-symmetrical to each other. Thebeveled edges of the two or more piercing elements can be at an acute oroblique angle relative to each other.

In some cases, two or more piercing elements can be supported by aholder in a predefined configuration. The two or more piercing elementscan have predefined orientations relative to each other. The two or morepiercing elements can comprise beveled edges that are oriented relativeto each other in a predefined manner. The beveled edges of the two ormore piercing elements can be symmetrical to each other.

In some embodiments, the piercing elements can comprise two or morelancets. Optionally, the piercing elements can comprise needles and/ormicroneedles. In some cases, two or more lancets can have a same bevelangle. Alternatively, two or more lancets can have different bevelangles. In some cases, the bevel angle(s) can range from about 10degrees to about 60 degrees. In some cases, the two or more lancets cancomprise beveled faces having a same bevel length. Alternatively, thetwo or more lancets can comprise beveled faces having different bevellengths. In some cases, the bevel length(s) can range from about 2 mm toabout 10 mm.

In some embodiments, two or more piercing elements can be configured togenerate cuts on the skin that extend in different directions along theskin and that are non-parallel to each other.

In some embodiments, the deployment spring can be configured to move andcause the piercing elements to penetrate the skin of the subject atspeeds ranging from about 0.5 m/s to about 2.0 m/s. The deploymentspring can be configured to move and cause the piercing elements topenetrate the skin of the subject with a force ranging from about 1.3 Nto about 24.0 N. A spring-force of the retraction spring can be lessthan a spring-force of the deployment spring. In some cases, thedeployment spring can have a spring-rate of about 2625 N/m, and theretraction spring can have a spring-rate of about 175 N/m. Thedeployment spring can be configured to cause the one or more piercingelements to penetrate the skin to depths ranging from about 0.5 mm toabout 3 mm. The retraction spring can be configured to retract thepiercing elements from the skin of the subject at speeds ranging fromabout 0.1 m/s to about 1.0 m/s.

In some embodiments, the device can further comprise: a vacuum activatorconfigured to activate a vacuum for drawing the skin into a recess ofthe device. In some cases, a piercing activator can be configured toactivate the deployment spring only after the vacuum activator isactivated.

In some further aspects, a device for monitoring fluid sample collectionfrom a subject is provided. The device can comprise: a housingcomprising a cartridge chamber; a cartridge operably coupled to thecartridge chamber; components for penetrating skin of the subject anddrawing the fluid sample from the skin into the cartridge; and a flowmeter on the housing that enables the subject or a user to monitor aprogress of the fluid sample collection in real-time as the fluid sampleis collected into the cartridge.

In some aspects, a method for monitoring fluid sample collection from asubject can comprise: providing (1) a housing comprising a cartridgechamber, (2) a cartridge operably coupled to the cartridge chamber, (3)components for penetrating skin of the subject and drawing the fluidsample from the skin into the cartridge, and (4) a flow meter on thehousing; and monitoring, with aid of the flow meter, a progress of thefluid sample collection in real-time as the fluid sample is collectedinto the cartridge.

In some embodiments, the flow meter can be provided on a lid covering abase of the housing. The flow meter is not obscured by a cover of thehousing. The flow meter can be in proximity to the cartridge chamber.The flow meter can be substantially aligned with a cartridge locatedwithin the cartridge chamber. In some embodiments, the flow meter cancomprise a plurality of windows disposed parallel to a longitudinal axisof the cartridge. The plurality of windows can be made of an opticallytransparent material. The fluid sample can be visible through thewindows and sequentially fills each window as the fluid sample is beingcollected into the cartridge. Each window can be indicative of a knownamount of fluid sample that is collected. The fluid sample collection iscomplete when the fluid sample is visible in all of the windows. Theplurality of windows can comprise three or more windows.

In some embodiments, the flow meter can comprise a single windowdisposed parallel to a longitudinal axis of the cartridge. The windowcan be made of an optically transparent material. The fluid sample canbe visible through the window and continuously fills the window as thefluid sample is being collected into the cartridge. The fluid samplecollection is complete when the fluid sample is visible throughout thewindow.

In some further aspects, a cartridge assembly is provided. The cartridgeassembly can comprise: a cartridge for holding one or more matrices forstoring a fluid sample thereon; a cartridge holder releasably coupled tothe cartridge, wherein the cartridge assembly is releasably coupled to adevice used for collecting the fluid sample.

In some embodiments, a device for collecting a fluid sample from asubject is provided. The device can comprise: a housing comprising adeposition chamber and a pre-evacuated vacuum chamber, wherein thedeposition chamber is configured to receive and releasably couple to thecartridge assembly, and the deposition chamber is in fluidiccommunication with the vacuum chamber.

In some embodiments, a fluid sample collection kit can comprise thedevice and the cartridge assembly. In some embodiments, a fluid samplecollection assembly can comprise the device and the cartridge assemblyreleasably coupled to said device. In some embodiments, an input port ofthe cartridge can be releasably coupled to and in fluidic communicationwith a channel of the device, and the fluid sample can be collected frompenetrated skin of the subject and transported through the channel intothe cartridge.

In some embodiments, a method for collecting a fluid sample from asubject can comprise: releasably coupling the cartridge assembly to thedevice; placing the device adjacent to skin of the subject; activatingvacuum in the vacuum chamber to draw the skin into a recess of thehousing; using one or more piercing elements of the device to penetratethe skin; maintaining the device adjacent to the skin for a sufficientamount of time to draw the fluid sample into the device and collect thefluid sample into the cartridge; and decoupling the cartridge assemblyfrom the device after a certain amount of the fluid sample has beencollected in the cartridge.

In some embodiments, the cartridge holder can be releasably coupled tothe cartridge via a quick release mechanism. In some cases, the quickrelease mechanism can comprise one or more spring-clips on the cartridgeholder. The cartridge assembly can be capable of being coupled to anddetached from the deposition chamber without use of tools. The cartridgeassembly can be capable of being coupled to and detached from thedeposition chamber using no more than two motion steps. The cartridgeassembly can be coupled to the deposition chamber prior to thecollection of the fluid sample from the subject. The cartridge assemblycan be decoupled from the deposition chamber after the fluid sample fromthe subject has been collected into the cartridge.

In some embodiments, the cartridge can comprise two or more matrices forcollecting and storing the fluid sample thereon. The two or morematrices can be disposed in a configuration that permits the fluidsample to wick between and along the two or more matrices. For example,the two or more matrices can be disposed substantially parallel to eachother. In some cases, the two or more matrices can be separated by a gapof about 0.5 mm. In some cases, at least one of the matrices can becapable of collecting at least 60 uL of fluid sample. In some cases,each of two or more matrices can be capable of collecting at least 60 uLof fluid sample.

In some embodiments, the cartridge can further comprise one or moreabsorbent pads configured to be in fluidic communication with the one ormore matrices, wherein the one or more absorbent pads can be used tohold excess fluid sample. The one or more absorbent pads can aid inensuring that a predefined volume of the fluid sample can be collectedand maintained on the one or more matrices, regardless of an inputvolume of the fluid sample into the cartridge up to a predefined range.In some cases, the one or more matrices can include two matrices thatare each configured to hold up to about 7 uL of the fluid sample. Eachof the two matrices can be configured to hold and maintain about 75 uLof the fluid sample as the input volume of the fluid sample to thecartridge increases beyond 150 uL up to the predefined range. In somecases, the predefined range can be from about 150 uL to about 300 uL. Inother cases, the predefined range can be greater than 300 uL. In somecases, the one or more absorbent pads can be capable of holding at least100 uL of excess fluid sample.

In some embodiments, the cartridge holder can comprise a cartridge tabthat is configured to be releasably coupled to a distal end of thedeposition chamber. The cartridge tab can be configured such that thesubject or a user is able to (1) support the cartridge assembly byholding the cartridge tab, (2) couple the cartridge assembly to thedevice by pushing the cartridge tab, and/or (3) decouple the cartridgeassembly from the device by pulling the cartridge tab.

In some further aspects, a transportation sleeve is provided. The sleevecan comprise: an opening configured to couple to a cartridge tabincluded with the cartridge; and a dual support-release mechanism withinthe sleeve, wherein the dual support-release mechanism can comprise: (a)a retention element configured to engage with a corresponding matingfeature on the cartridge and secure the cartridge within the sleeve, and(b) a release element configured to cause the spring-clips on thecartridge holder to release and thereby decouple the cartridge from thecartridge holder. The dual support-release mechanism can permit thecartridge holder to be removed from the opening of the sleeve while thecartridge is secured in place within the sleeve, without exposure of thestrips to the ambient environment. In some cases, the transportationsleeve can further comprise a desiccant within the sleeve. In somecases, the sleeve can be sized and shaped to accommodate user or patientidentity (ID) labels.

In some embodiments, a transportation assembly can comprise: thetransportation sleeve, and the cartridge coupled to said transportationsleeve. In some cases, the cartridge tab can be configured tohermetically seal the opening of the sleeve.

In some embodiments, the cartridge can be oriented such that the flow ofthe fluid sample into the cartridge is further aided with gravity. Insome cases, the cartridge can comprise a luer-type fitting that canengage with the device when the cartridge is inserted into thedeposition chamber.

In some embodiments, the one or more matrices can comprise absorbentpaper. In some cases, one or more of the matrices can comprisestabilization chemistry. In some cases, a first matrix can comprise afirst stabilization chemistry and a second matrix can comprise a secondstabilization chemistry different from the first stabilizationchemistry. In some alternative cases, one or more of the matrices doesnot comprise stabilization chemistry.

Provided herein are medical systems, devices, and methods for samplecollection and storage. The disclosed systems, devices, and methods cancomprise structure features that facilitate sample collection (e.g.blood collection devices) as well as components for collecting bloodsample on to substrate for storage and transport.

Any of the devices disclosed herein can rely on the generation of avacuum to apply negative pressure to deform the skin of a subject and toapply local suction directly to the sample collection site, therebyfacilitating sample flow and collection. Any of the devices disclosedherein can comprise a concave cavity that can be placed at the surfaceof the skin of the subject, this concave cavity can be configured todeliver vacuum (e.g. negative pressure, suction etc.) to the skin of thesubject. Any of the devices disclosed herein can comprise an openingdisposed at the apex of or other surface of the concave cavity, theinner diameter can be configured to allow a piercing element to piercethe skin of the subject; and a piercing element can be configured topass through the inner diameter. Local suction can be applied to thesample collection site through the inner diameter.

In some embodiments, a vacuum can be configured to deform the skin ofthe subject using different mechanisms, for example the vacuum can beconfigured to draw the skin of the subject into the concave cavity. Aconcave cavity can be configured to constrain the surface of the skinagainst its entire or a portion of its concave surface of the subject atwhich point the piercing element can be configured to pierce the skin ofthe subject. An opening contiguous with a cylinder (e.g. a cylinder influid contact with a cartridge) can be configured to draw the blood fromthe subject into the device when the vacuum is applied to the skin ofthe subject and after an incision has been made in the skin of thesubject.

Vacuum pressure can be generated using an evacuated vacuum chamberconfigured such that activation of the device pierces the evacuatedvacuum chamber forming negative pressure that draws the blood from thesubject through the opening and channels and into a cartridge and onto asolid matrix for sample storage vacuum pressures can be in the range ofbetween 1-20 psi. The vacuum pressure can be about 5 psi. Vacuum chambervolume can be within a 10%-100% margin of twice the volume of thecombined concave cavity, opening, channel and cartridge volume. Any ofthe devices disclosed herein can comprise a vacuum activation actuatorconfigured to activate the vacuum upon actuation of the vacuumactivation actuator. The vacuum activation actuator can comprise abutton.

Any of the devices disclosed herein can be configured for drawing aspecific volume (e.g. greater than 20 μL, greater than 40 μL, greaterthan 60 μL, greater than 80 μL, greater than 100 μL, greater than 150μL, or greater than 200 μL) of blood (e.g. capillary blood) from asubject in defined period of time (e.g. less than 4 minutes), can havespecific vacuum and device parameters. The structure of the concavecavity can have an impact on blood collection, for example the rate ofblood sample collection can be dependent on the curvature and size ofthe concave cavity and the vacuum pressure.

To facilitate blood collection the surface area acted on by the vacuumcan have specific parameters, for example the surface area of the skinunder vacuum and in contact with the concave cavity can be within a 10%margin of 500 mm² and the opening in fluid contact with a cylinder (e.g.a cylinder in fluid contact with a cartridge) can have a diameter can bewithin a 10% margin of 8 mm². Any of the devices, systems and methodsherein for collecting sample (e.g. blood samples) can be configured witha removable cartridge. The removable cartridge can be held in fluidcommunication with the cylinder (e.g. the cylinder in contact with theopening in the concave cavity). Any of the devices disclosed herein cancomprise a visual metering window configured to permit visualization ofthe removable cartridge while the removable cartridge is in the device.Any of the devices disclosed herein can comprise a piercing module,wherein the piercing module comprises one or more piercing elements. Thepiercing elements can be actuated with a button. Before and afteractuation, the piercing element can be withdrawn when the piercingelement is in an unactivated state.

Also disclosed herein are cartridges configured to collect sample fromthe device and transfer it to solid substrate such that precise volumesof sample are collected on and metered by the absorbency of the solidsubstrate. For example, the standardized quantity of blood saturatingeach strip of the substrate can be within the range of 50-100 uL on asubstrate with surface area within the range of 100-300 squaremillimeters. A cartridge can comprise a channel disposed between twostrips of substrate configured for transferring a blood sample to thetwo strips of substrate. A cartridge can comprise a spacer disposedbetween a portion of each of the two strips of substrate. A spacer canbe configured to adjust the space between the two strips of substratedepending on one or more conditions. Cartridges can be removable fromthe device, for example using methods to clip the cartridge into place.Cartridges can further comprise a wicking tail. A wicking tail can beconfigured for standardizing the quantity of blood saturated on the twostrips of substrate.

Collecting standardized quantities of blood on substrate of specificsurface area can be performed using various methods. Methods forapplying blood to at least two solid supports can comprise the steps ofproviding a cartridge comprising at least two solid supports. Theprovided cartridge can comprise at least two solid supports aresubstantially the same size, such that a surface of each of the at leasttwo solid supports face each other and the surface at the least twosolid supports are substantially parallel to each other. The at leasttwo solid supports can be separated by a defined distance (e.g. within10% margin of 0.4 mm), and the cartridge can be configured so that achannel is formed between the two solid supports. Blood can be passinginto the tunnel between the at least two solid supports, wherein theblood is absorbed to each of the at least two solid supports as itpasses through the tunnel between the at least two solid supports. Solidsupports used in these methods can comprise fixed dimensions (e.g. widthbetween 3 mm and 10 mm and length between 3 mm and 26 mm). The cartridgeused in the method can further comprise a wicking element configured formetering blood flow through the device.

Additional aspects and advantages of the present disclosure will becomereadily apparent to those skilled in this art from the followingdetailed description, wherein only illustrative embodiments of thepresent disclosure are shown and described. As will be realized, thepresent disclosure is capable of other and different embodiments, andits several details are capable of modifications in various obviousrespects, all without departing from the disclosure. Accordingly, thedrawings and description are to be regarded as illustrative in nature,and not as restrictive.

INCORPORATION BY REFERENCE

All publications, patents, and patent applications mentioned in thisspecification are herein incorporated by reference to the same extent asif each individual publication, patent, or patent application wasspecifically and individually indicated to be incorporated by reference.

BRIEF DESCRIPTION OF THE DRAWINGS

The novel features of the invention are set forth with particularity inthe appended claims. A better understanding of the features andadvantages of the present invention will be obtained by reference to thefollowing detailed description that sets forth illustrative embodiments,in which the principles of the invention are utilized, and theaccompanying drawings of which:

FIG. 1A is a perspective view of a sample acquisition device inaccordance with some embodiments;

FIG. 1B shows a recess of the device for skin suction;

FIG. 1C shows a flow meter of the device for monitoring the progress ofsample collection;

FIG. 1D shows a removable cartridge assembly for sample collection;

FIG. 2A shows a perspective view of a housing base assembly of thedevice;

FIG. 2B shows a perspective view of a housing cover of the device;

FIG. 2C shows another perspective view of the device;

FIG. 3A shows a side sectional view of the device prior to insertion ofthe cartridge assembly;

FIG. 3B shows a top view of the device of FIG. 3A;

FIG. 4A shows a side view of the device after insertion of the cartridgeassembly;

FIG. 4B shows a top sectional view of the device of FIG. 4A;

FIG. 5A shows a side sectional view of the device placed on a subject'sskin without vacuum activation;

FIG. 5B shows a schematic block diagram corresponding to the device ofFIG. 5A;

FIG. 6A shows the subject's skin being drawn into the recess undervacuum pressure;

FIG. 6B shows a schematic block diagram corresponding to the device ofFIG. 6A;

FIG. 7A shows a piercing activator of the device in a locked state;

FIG. 7B shows the piercing activator of the device in an unlocked state;

FIG. 8A shows the subject's skin being penetrated by piercing elementsafter the piercing elements have been deployed;

FIG. 8B shows a schematic block diagram corresponding to the device ofFIG. 8A;

FIG. 9A shows blood being drawn from the cuts on the skin after thepiercing elements have been retracted;

FIG. 9B shows a schematic block diagram corresponding to the device ofFIG. 9A;

FIG. 10A shows the preferential and enhanced flow of blood from the cutstowards the cartridge in the deposition chamber of the device;

FIG. 10B shows a schematic block diagram corresponding to the device ofFIG. 10A;

FIGS. 11A and 11B show schematic block diagrams of a sample acquisitiondevice prior to insertion of a cartridge assembly;

FIGS. 12A and 12B show schematic block diagrams of the device afterinsertion of the cartridge assembly;

FIGS. 13A and 13B show the device of FIGS. 12A/12B being placed on asubject's skin;

FIGS. 14A and 14B show the equalization of pressures and the subject'sskin being drawn into the recess, upon piercing the foil separating thevacuum chamber and the deposition chamber;

FIGS. 15A and 15B show the subject's skin being completely drawn intothe recess by negative pressure;

FIG. 16A shows the deployment of the piercing elements and penetrationof the subject's skin in the recess;

FIG. 16B shows the subject's skin being penetrated and the retraction ofthe piercing elements;

FIG. 16C shows the initial flow of blood from the cuts on the skin;

FIG. 16D shows the blood being drawn towards the cartridge in thedeposition chamber with aid of the vacuum, pressure differentials, andgravitational force;

FIG. 16E shows the preferential flow of blood towards the depositionchamber, and the wicking of blood along matrices in the cartridge;

FIG. 16F shows the blood absorbed onto the matrices, and completion ofthe blood collection;

FIGS. 17A, 18A, and 19A show schematic block diagrams of blood flowalong the matrices in the cartridge at different stages of the bloodcollection;

FIGS. 17B, 18B, and 19B illustrate a flow meter indicating the progressof the blood collection in accordance with some embodiments;

FIGS. 17C, 18C, and 19C illustrate a flow meter indicating the progressof the blood collection in accordance with some other embodiments;

FIG. 20A shows a top view of a device with the flow meter indicatingthat the blood collection has been completed;

FIG. 20B is a schematic block diagram corresponding to the device ofFIG. 20A prior to removal of the filled cartridge assembly;

FIG. 21A shows a top view of the device with the filled cartridgeassembly removed;

FIG. 21B is a schematic block diagram corresponding to the device ofFIG. 21A with the filled cartridge assembly removed;

FIG. 22A shows a perspective view of a transportation sleeve;

FIG. 22B shows a top view of the transportation sleeve and a filledcartridge assembly prior to its insertion into the sleeve;

FIG. 22C shows the filled cartridge assembly inserted into thetransportation sleeve;

FIG. 23 shows an exploded view of the transportation sleeve andcartridge assembly;

FIG. 24A shows a side sectional view of the transportation sleeve withcartridge assembly inserted therein;

FIG. 24B shows a side sectional view with the cartridge holder removed,leaving the cartridge within the transportation sleeve;

FIGS. 25A and 25B show an exemplary procedure of collecting bloodsamples from a subject using a sample acquisition device, and packagingof the blood samples for shipment;

FIG. 26 shows an exploded view of certain components of the sampleacquisition device;

FIG. 27A shows different views of a piercing elements;

FIG. 27B shows the piercing elements being supported by a holder;

FIG. 28A shows different views of a deployment spring;

FIG. 28B shows different views of a retraction spring;

FIG. 29 shows different views of two matrices separated by spacers withan absorbent pad on one end;

FIG. 30 shows examples of different types of recesses that can be usedin a sample acquisition device;

FIG. 31A, FIG. 31B, FIG. 31C, and FIG. 31D illustrates features that canbe included in a device or device for collecting a blood sample;

FIG. 32A, FIG. 32B, FIG. 32C, and FIG. 32D illustrate front, side, andback views of a device that can be used to collect a sample of definedvolume and store it on a removable stabilization matrix;

FIG. 33A, FIG. 33B, and FIG. 33C illustrate features of a device thatcan be used to enhance sample collection;

FIG. 34A, FIG. 34B, FIG. 34C, and FIG. 34D illustrate an embodiment of adevice for collecting a blood sample from a subject, and means forstoring the sample in a removable cartridge;

FIG. 35 illustrates an inside view of a removable cartridge that can beused with any of the disclosed sample collection devices (e.g., samplecollection devices illustrated in FIGS. 31A-31D, FIGS. 32A-32D, FIGS.33A-33C, and FIGS. 34A-34D);

FIG. 36A and FIG. 36B illustrate an exemplary orientation of a device ordevice configured to use one or more mechanisms (e.g. gravity, capillaryaction, global vacuum, and local suction) collect and deposit a bloodsample on a solid matrix for storage;

FIG. 37A, FIG. 37B, FIG. 37C, and FIG. 37D illustrate a modular designof an device with components configured for generating a vacuum, lancinga subject's skin, collecting, metering and stabilizing a blood samplefrom the subject, and storing the collected sample;

FIG. 38A illustrates external features of an exemplary low profileembodiment of a device provided herein;

FIG. 38B illustrates internal workings of a device provided herein in anexemplary starting position, when the device is not activated;

FIG. 38C illustrates internal workings of a device provided herein oncethe button is depressed (1), and the blade holder is released (2);

FIG. 38D illustrates internal workings of a device provided herein at anend of a travel path of a blade holder, where the collection arm isreleased by a latch that makes contact with the blade holder at the endof the travel path;

FIG. 38E shows a side view of a device provided herein, providing a viewof a release mechanism for a blood collection arm;

FIG. 38F illustrates a released blood collection arm creating a sealaround cuts created by blades shown in FIG. 38E;

FIG. 39A, FIG. 39B, FIG. 39C, FIG. 39D, and FIG. 39E illustrate top,bottom, side and internal views of an exemplary low profile bloodcollection device;

FIG. 40A, FIG. 40B, FIG. 40C, and FIG. 40D illustrate various views of ablood collection device and components thereof configured for lancing asubject using vertical cutting, and extracting a sample from the subjectusing a syringe;

FIG. 41A illustrates a safety mechanism that can be used to preventinadvertent blade deployment of a blood sample collection device forcollecting a sample that relies on vertical cutting using a rotatableblade;

FIG. 41B illustrates a mechanism for collecting a sample using a bloodcollection device that relies on vertical cutting using a rotatableblade;

FIG. 42A, FIG. 42B, and FIG. 42C illustrates a device and mechanism forcollecting a sample using a spring loaded blade rotatable blade toperform vertical cutting;

FIG. 43A and FIG. 43B illustrates a device for applying global vacuumand local suction to collect an appropriate amount of sample within adesired period of time (e.g. at a rate that falls within a desiredrange);

FIG. 44A and FIG. 44B illustrate two views of a device forsimultaneously lancing a subject and forming a seal;

FIG. 45A, FIG. 45B, and FIG. 45C illustrate an exemplary vacuum chamberthat can be used with any of the devices and methods disclosed herein;

FIG. 46A, FIG. 46B, and FIG. 46C illustrate an exemplary chamber forcollecting, metering, storing and stabilizing a sample, and mechanismsfor driving sample through the chamber and onto the solid matrices forstoring the sample;

FIG. 47 illustrates the components of a system configured for collectinga blood sample using a sample collection device and a removable samplestorage cartridge;

FIG. 48 illustrates steps that a subject or clinician might take tocollect and provide a sample to a facility for analysis;

FIG. 49 illustrates steps that a lab (e.g. a CLIA certified lab or otherfacility) might perform to prepare a sample for analysis;

FIG. 50A, FIG. 50B, and FIG. 50C illustrate a visual metering windowpermitting a user to view draw progress (FIG. 50A illustrates visuallytracking by the health care provider (HCP) as the stabilization matrixstrip fills. When the final window fills, the draw is complete.

FIG. 50B illustrates a wicking pad capturing excess blood. FIG. 50Cillustrates varying levels of blood deposition on matrix strips.);

FIG. 51 illustrates the percentage of HbA1c in blood samples of fivedifferent volumes (30 μL, 45 μL, 60 μL, 75 μL, 100 μL) drawn from twodifferent donors;

FIG. 52 illustrates a flow chart of a clinical trial to access precisionof blood tests done using blood drawn with devices disclosed hereincompared to venipunctures;

FIG. 53 illustrates principles of operation and use flow of a device;

FIG. 54 illustrates HbA1c as a percent of total hemoglobin (Y-axis) forvarious experimental conditions (X-axis) (For each condition, theaverage of the replicate measurements is plotted as a black bar andsample measurements are shown as open circles. The dotted linesdelineate ±6% relative error around the Day-0 average measurement.);

FIG. 55 illustrates HbA1c as a percent of total hemoglobin (Y-axis) forvarious experimental conditions (X-axis) (Four individual, Day-0, liquidwhole-blood, replicates for each donor are plotted as circles. Twotechnical replicates for each dried blood spot (DBS)-strip are averagedand the resulting DBS-strip averages are also plotted as circles. Foreach experimental condition, the average of all measurements is plottedas a black bar. Dotted lines delineate ±% relative error around thedonor-specific, Day-0, average measurements.); and

FIG. 56 illustrates an exemplary procedure to collect and store bloodusing a device described herein.

DETAILED DESCRIPTION

Reference will now be made in detail to exemplary embodiments of thedisclosure, examples of which are illustrated in the accompanyingdrawings. Wherever possible, the same reference numbers will be usedthroughout the drawings and disclosure to refer to the same or likeparts.

I. General

Provided herein are devices, methods, and kits for collecting a fluidsample, e.g., from a subject's body. The fluid sample can be, forexample, blood drawn from penetrated skin of the subject. The devicesdisclosed herein can be handheld and user-activable, and suitable foruse outside of traditional healthcare facilities, for example in homes,in remote locations, while a subject is traveling, etc. The devices canbe portable and easy to use, and allow individuals to efficiently andreliably collect their own blood samples, without relying on trainedhealthcare personnel, and without requiring the individual to have anyprior blood draw training experience. The devices and methods describedherein can be minimally invasive and permit lower levels of pain (orperception of pain) in a subject relative to use of other devices andmethods, which can help to improve the overall blood draw experience forthe subject. Kits can be provided with detailed instructions that guideusers on how the devices can be used for blood sample collection andstorage. Optionally in any of the embodiments disclosed herein, the kitscan include transportation sleeves and pouches forshipping/transportation of cartridges to testing facilities. A cartridgecan be configured to support one or more matrices configured to hold atleast a predefined volume of collected blood.

Notably, the sample acquisition devices and methods disclosed herein canenhance collection of a fluid sample (e.g., blood) from the subject. Thedisclosed sample acquisition devices and methods can be capable ofdrawing blood at increased flowrates and higher sample volumes beginningfrom time of skin incision, compared to currently available non-venousblood collection devices and methods. According to various embodimentsof the present disclosure, an average collection flowrate and collectedsample volume can be increased with aid of a number of features, e.g., arecess that is configured or optimally designed for skin suction,vacuum, pressure differentials, aid of gravitational force, wicking orcapillary effects, as described in further detail herein. Additionally,the embodiments disclosed herein are advantageous over currentlyavailable non-venous blood collection devices and methods, in that thedisclosed devices and methods can permit stabilization of controlledvolumes of blood samples to be deposited on one more matrix strips.Further advantages of the disclosed embodiments can include ease ofsample removal from a sample acquisition device, and the packaging ofthe removed sample for subsequent transportation to testing facilities.

Samples, e.g., blood samples, collected using the sample acquisitiondevices and methods described herein can be analyzed to determine aperson's physiological state, for detecting diseases and also formonitoring a health condition of the user. Individuals can rapidlyevaluate their physiological status, since samples, e.g., blood samplescan be quickly collected using the disclosed devices and methods, andthe samples, e.g., blood samples can be either (1) analyzed on the spotusing, for example, immunoassays or (2) shipped promptly to a testingfacility. The reduced lead-time for blood collection, analysis andquantification can be beneficial to many users, e.g., users who havecertain physiological conditions/diseases that require constant andfrequent blood sample collection/monitoring.

Various aspects of the devices, methods, and kits described herein canbe applied to any of the particular applications set forth herein andfor any other types of fluid sample devices, in addition to bloodcollection devices. The devices, methods, and kits can be used in anysystem that requires a fluid sample to be drawn from the subject's body.The devices, methods, and kits described herein can be applied as astandalone apparatus or method, or as part of a medical system in ahealthcare environment. It shall be understood that different aspects ofthe devices, methods, and kits described herein can be appreciatedindividually, collectively, or in combination with each other.

II. Sample Acquisition Devices

FIGS. 1A-1D illustrate sample acquisition device 100 in accordance withsome embodiments. A sample acquisition device as described herein canrefer to any apparatus, device or system that is designed, configured,or used for collecting, storing, and/or stabilizing a fluid sample,e.g., a fluid sample drawn from a subject. In various aspects, thesample is a biological sample. Non-limiting examples of biologicalsamples suitable for use with the devices of the disclosure can includewhole blood, blood serum, blood plasma, and the like.

The devices herein can be used in a variety of environments andapplications including an individual's own home, remote locations,on-site or while traveling, personalized healthcare, point-of-care(POC), hospitals, clinics, emergency rooms, patient examination rooms,acute care patient rooms, ambulatory care, pediatrics, fieldenvironments, nurse's offices in educational settings, occupationalhealth clinics, surgery or operation rooms.

In some of the embodiments described herein, a sample acquisition deviceis preferably used to collect and store a sample, e.g., blood, drawnfrom a subject. A subject as described herein can be an individual, auser, an end user, a patient, and the like. A subject can be an animal,preferably a primate or a non-primate. A subject can be a male orfemale. A subject can be pregnant, suspected of being pregnant, orplanning to become pregnant. A subject can be ovulating. A subject canhave a condition, e.g., cancer, autoimmune disease, or diabetes. A humancan be an infant, child, teenager, adult, or elderly person. In certainembodiments, the mammal is 0 to 6 months old, 6 to 12 months old, 1 to 5years old, 5 to 10 years old, 10 to 15 years old, 15 to 20 years old, 20to 25 years old, 25 to 30 years old, 30 to 35 years old, 35 to 40 yearsold, 40 to 45 years old, 45 to 50 years old, 50 to 55 years old, 55 to60 years old, 60 to 65 years old, 65 to 70 years old, 70 to 75 yearsold, 75 to 80 years old, 80 to 85 years old, 85 to 90 years old, 90 to95 years old or 95 to 100, or over 12 years old, over 16 years old, over18 years old, or over 21 years old.

The sample acquisition devices herein can be easily and convenientlyused by a subject to draw a sample, e.g., blood sample, without the helpor aid of others. Optionally in some cases, the device can be used by athird party to collect blood from a subject. A third party can include,for example a family member of the subject, trained medicalprofessionals such as physicians and nurses, Emergency MedicalTechnicians (EMTs), clinicians, laboratory technicians, untrainedmedical personnel, etc. Optionally in any of the embodiments disclosedherein, a third party can be a non-living entity, e.g. a robot.

The device can be designed such that it is minimally invasive andgenerates a low level of pain (or reduced perception of pain) in theusers. For example, the device can include a low number (e.g. one ortwo) piercing elements, instead of an array of multiple (three, four,five or more) needles or microneedles for penetrating the skin.Optionally, a device need not be pre-packaged with one or more piercingelements. For example, a variety of piercing elements can be operablyand releasably coupled to the device, and/or interchanged onto thedevice e.g., after each use. In some alternate cases, a device can beoperated without using piercing elements. For example, a subject's skincan have one or more pre-existing cuts, and the device can be placedover the one or more pre-existing cuts to draw blood using skin suctionand vacuum pressure.

The device can be portable, disposable and designed for use in a singlepatient encounter. Optionally in any of the embodiments disclosedherein, the device can be re-usable. For example, a device can be usedmore than once, for example twice, three, four, five, five, six, seven,eight, nine, ten or more times. Optionally in any of the embodimentsdisclosed herein, a single device can be used in multiple patientencounters, either with a same subject or with a plurality of differentsubjects. The device can be of a form factor and ergonomically designedto facilitate the sample collection process. Sample collection,treatment and storage can be performed on a single device. In somecases, sample collection, treatment and storage can be performed usingmultiple components or devices (e.g., a piercing module and a vacuummodule can be provided as separate devices that are operably connectedor coupled together via one or more channels).

In some embodiments, a sample acquisition device can be configured orcapable of collecting at least 150 uL of blood from a subject within atime window beginning from time of incision or penetration of a skinportion of the subject. The time window can be less than 5 minutes,preferably less than 3 minutes. In some embodiments, the time window canbe under 2 minutes. Optionally in any of the embodiments disclosedherein, the time window can be under one minute. The device is capableof collecting a larger volume of blood at higher average flowratescompared to currently available non-venous collection devices.

In some other embodiments, a sample acquisition device can be configuredto collect smaller amounts of blood (e.g. less than 150 uL, 140 uL, 130uL, 120 uL, 110 uL, 100 uL, 90 uL, 80 uL, 70 uL, 60 uL, 50 uL, 40 uL, 30uL, or 25 uL) of blood from a subject within a time window beginningfrom time of incision or penetration of a skin portion of the subject.The time window can be less than 5 minutes, preferably less than 3minutes. In some embodiments, the time window can be under 2 minutes.Optionally in any of the embodiments disclosed herein, the time windowcan be under one minute.

FIGS. 1A, 1B, 1C, and 1D illustrate different views of an exemplarysample acquisition device 100. Specifically, FIG. 1A shows an overallperspective view of the device. The device can include a housing 102.The housing can include a housing base 110 and a housing cover 152operably coupled to each other. The housing base can encompass a vacuumchamber and a deposition chamber as described further herein.

Optionally in any of the embodiments disclosed herein, a housing can beprovided separately from the components of the device, and the housingneed not be part of or integrated with the components. For example, avacuum chamber, deposition chamber, cartridge chamber, and/or cartridgeassembly as described elsewhere herein can be operably coupled to aseparately provided housing. A recess as described herein can beprovided on a portion of the housing. A housing can include a casing,enclosure, shell, box, and the like. A housing can include one or morehollow chambers, cavities or recesses. The housing may be formed havingany shape and/or size. The housing can be configured to support one ormore components as described elsewhere herein. Additionally oroptionally, one or more of the components can serve or function as thehousing. The housing can be integrated with one or more of thecomponents herein, or one or more of the components can be integratedwith or into the housing. The housing can be configured for mountingonto a surface such as, for example, skin of a subject. Optionally inany of the embodiments disclosed herein, a bracket or strap can beprovided that allows the housing to be mounted to a surface.

The device can include a vacuum activator 114. The vacuum activator caninclude a button 115 located on the housing base. In some cases, thedevice does not have a vacuum activator or need not have a vacuumactivator (e.g., the device can be configured to automaticallyconfigured to provide a vacuum upon sensing contact to an appropriatesurface, without requiring a user to manually or semi-manually activatea vacuum activator). The device can further include a piercing activator166. The piercing activator can include a button 167 located on thehousing cover. In some cases, the device does not have a piercingactivator or need not have a piercing activator (e.g., the device can beused to draw blood from skin that has already been penetrated or pre-cutby other discrete stand-alone piercing elements). The piercing activatorcan be preferably activated after the vacuum activator has beenactivated. In some cases, the piercing activator can be activatedindependently of the vacuum activator or vacuum state of the device. Insome embodiments, the piercing activator can be locked prior to use ofthe device, and the piercing activator can be activated only after thevacuum activator has been activated. In some cases, the vacuum activatoris locked prior to use of the device, and the vacuum activator can beactivated only after the piercing activator has been activated. Thepiercing activator (e.g., button 115) and vacuum activator (e.g., button167) can be located on the same side or face of the housing.Alternatively, the piercing activator (e.g., button 115) and vacuumactivator (e.g., button 167) can be located on different sides or facesof the housing. The device 100 or any of the devices herein can furtherinclude a cartridge assembly 180. Such cartridge assembly can bereleasably coupled to the device and detached from the device. As shownin FIG. 1A, a cartridge tab 192 of the cartridge assembly can protrudefrom an edge of the device. Optionally in any of the embodimentsdisclosed herein, the cartridge tab and the piercing activator/vacuumactivator (e.g., buttons 115/167) can be located on different sides(e.g. opposite ends) of the housing. Additional details about the vacuumactivator and the piercing activator are described herein.

FIG. 1B shows a bottom perspective view of the device, in particular arecess 136 provided on the housing base 110. The recess can be a concavecavity. The recess can have a cup-like shape. Optionally in any of theembodiments disclosed herein, the recess can have a substantiallyhemispherical shape. The housing base can be configured to be placed andreleasably attached onto a portion of a subject's body, for example onthe subject's upper arm. A portion of a subject's skin can be drawn intothe recess with aid of vacuum pressure, e.g., as described elsewhereherein. The recess can be configured having a shape and/or size thatenables an increased volume of a fluid sample (e.g., blood) to becollected from a subject. The housing base can include a planar portion132 to be placed on the subject's skin. The planar portion can surroundthe periphery of the recess. The planar portion of the housing base canhave any shape. Optionally in any of the embodiments disclosed herein,the planar portion can include an annular ring-like shape. An adhesive(not shown) can be placed on the planar portion of the housing base topromote adhesion of the device to the subject's skin, and to create anairtight hermetic seal after the device has been placed onto the skin.Optionally in any of the embodiments disclosed herein, a fillet 138 canbe provided between the periphery of the recess and the planar portionof the housing base. The fillet can improve vacuum suction to the skinand reduce leaks. As shown in FIG. 1B, the recess can include an opening140. The opening can be located anywhere in the recess. For example, theopening can be located at an innermost portion of the recess. Optionallyin any of the embodiments disclosed herein, a fillet 139 can be providedat the periphery of the opening. Additional details about the recess,the opening, and suction of skin into the recess are described herein.

The opening 140 can be an opening of a lumen 142. The lumen can includea port 144 leading to a deposition chamber (not shown) located in thehousing base. Optionally in any of the embodiments disclosed herein, thelumen can include a cutout 145, and the port 144 can be provided withinor proximal to the cutout. The cutout 145 can help to reduce or preventocclusion of the port 144 by a subject's skin when the skin is drawninto the recess of the housing base. Keeping access to the port 144 open(e.g. by not having the port occluded or blocked by skin) can help toensure that blood drawn from a subject's skin is able to flow throughthe port 144 into the deposition chamber. The lumen can further includea port 150 leading to an enclosure for holding one or more piercingelements (not shown). The one or more piercing elements can beconfigured to extend out of the opening to penetrate the subject's skinwhen (or after) the skin is drawn into the recess by vacuum pressure.The one or more piercing elements can be subsequently retracted backinto the housing after penetrating the skin. Additional details aboutthe one or more piercing elements and their actuation are describedherein.

Blood can be drawn from cuts made on the skin. The blood can flow fromthe cuts through the port 144 towards a cartridge (not shown) located ina deposition chamber in the housing base. The flowrate and volume of theblood collection can be enhanced (e.g. increased) with aid of thevacuum, pressure differentials, gravitational force, andwicking/capillary effects, e.g., as described in detail elsewhereherein. The cartridge can include one or more matrices for collectingand storing a predefined volume of the blood. Additional details aboutthe enhanced fluid collection are described in various parts of theSpecification, for example in Section II Part G.

FIG. 1C shows a flow meter 170 of the device. The flow meter can includeone or more optically transparent windows 172. The flow meter can besubstantially aligned with the cartridge (specifically the matrices inthe cartridge) when the cartridge assembly is inserted into the device.The flow meter can allow the subject or another user to monitor aprogress of the sample (e.g., blood) collection in real-time as thesample is being collected into the cartridge. In some embodiments, theflow meter can be provided on a lid of the housing base. For example,the flow meter can be formed as part of the lid. The lid can be anintervening layer between the housing base and the housing cover. Thelid can cover the housing base, and seal a vacuum chamber in the housingbase. In some embodiments, the lid can be ultrasonically welded to thehousing base. The lid can provide an airtight hermetic seal. Additionaldetails about the flow meter are described, e.g., in Section II Part Fof the Specification.

FIG. 1D shows a cartridge assembly 180 that can be releasably coupled tothe device. The cartridge assembly can be part of the device, and can bedecoupled from the device. The cartridge assembly can be inserted into adeposition chamber (or cartridge chamber) of the housing base via anopening 128. The cartridge assembly can include a cartridge 182 and acartridge holder 190. The cartridge holder is configured to support thecartridge. The cartridge holder can include a cartridge tab 192, aseal/gasket 194, and spring clips 196. A subject or user can handle orhold the cartridge assembly using the cartridge tab. For example, thesubject can insert the cartridge assembly into the deposition chamber(cartridge chamber) of the device by pushing in the cartridge tab. Afterthe sample collection has been completed, the subject can remove thecartridge assembly from the deposition chamber (cartridge chamber) ofthe device by pulling the cartridge tab. The subject can also hold thecartridge assembly by the cartridge tab to avoid contamination to thecartridge and/or sample. The seal/gasket 194 can hermetically seal thedeposition chamber (cartridge chamber) once the cartridge assembly isproperly inserted into the device. The spring clips 196 allow thecartridge to be held in place by the cartridge holder.

The cartridge can be configured to support one or more matrices 186 onwhich the fluid sample (e.g., blood) is collected. In some embodiments,the cartridge can support two or more matrices. The two or more matricescan separated by one or more spacers. The cartridge can include acartridge port 184 and a channel (not shown) leading to the matrices.The cartridge can be configured to support one or more absorbent pads(not shown) for holding excess fluid. The absorbent pads help to ensurethat a predefined volume of fluid can be collected on each of thematrices. Additional details about the cartridge assembly are described,e.g., in Section II Part C of the Specification.

The housing base 110 and the housing cover 152 can each be separatelyprovided, and coupled together to form the housing. For example, FIG. 2Ashows a perspective view of the housing base 110 with a lid 124covering/sealing the housing base. The housing base can include a vacuumchamber 112 and a deposition chamber 126. The vacuum chamber and thedeposition chamber can be separated by one or more walls 125. The wallscan be substantially impermeable to fluids (e.g. gases and liquids). Thelid 124 can hermetically seal the vacuum chamber and the depositionchamber. The lid can include the flow meter 170. The deposition chambercan also serve as a cartridge chamber, and can be interchangeablyreferred to as such herein. A cartridge assembly 180 is shown insertedinto the deposition chamber (or cartridge chamber). The seal/gasket 194can hermetically seal the deposition chamber once the cartridge assemblyis fully inserted into the deposition chamber. FIG. 2B shows aperspective view of the housing cover 152. The housing cover can includea through-hole 153 through which the button 167 of the piercingactivator 166 can be inserted. The housing cover can include wings 155having a U or V-like shape to prevent obscuring the flow meter on thelid of the housing base. Accordingly, the housing cover can be shaped ina manner that allows a subject or another user to view the flow meterand monitor the progress of the fluid sample collection. The housingcover can have sufficient vertical (Z-height) clearance to permitplacement of a piercing module 154 therein. The piercing module cancomprise one or more piercing elements that are configured to extend andretract through the opening of the recess. FIG. 2C shows a perspectiveview of the assembled device 100 whereby the housing cover and thehousing base are coupled together. Exemplary means of attachment of thehousing cover to the housing base can include snapfits, ultrasonicwelding, nuts and bolts, rivets, screws, nails, locks, latches, wires,joints, soldering, welding, gluing and the like. In some alternativeembodiments, the housing base and housing cover can be monolithicallyand collectively formed as a single component.

The housing of the device can be formed having any shape and/or size.The housing or any components thereof can be formed using any number oftechniques known in the art such as injection molding, blow molding,three-dimensional (3D) printing, etc. The housing can include materialssuitable for healthcare applications (e.g., the housing material iscompatible for use with biological materials), depending on theparticular application. For example, components of the housing caninclude or be fabricated from materials such as cellophane, vinyl,acetate, polyethylene acrylic, butyl rubber, ethylene-vinyl acetate,natural rubber, a nitrile, silicone rubber, a styrene block copolymer, avinyl ether, or a tackifier. Optionally in any of the embodimentsdisclosed herein, the device can include antimicrobial and/or antisepticmaterials, for example sodium bicarbonate; hydrogen peroxide;benzalkonium chloride; chlorohexidine; hexachlorophene; iodinecompounds; and combinations thereof.

Optionally in any of the embodiments disclosed herein, one or morecomponents of the device can include or can be fabricated from materialssuch as polyvinyl chloride, polyvinylidene chloride, low densitypolyethylene, linear low density polyethylene, polyisobutene,poly[ethylene-vinylacetate] copolymer, lightweight aluminum foil andcombinations thereof, stainless steel alloys, commercially puretitanium, titanium alloys, silver alloys, copper alloys, Grade 5titanium, super-elastic titanium alloys, cobalt-chrome alloys, stainlesssteel alloys, superelastic metallic alloys (e.g., Nitinol, superelasto-plastic metals, such as GUM METAL® manufactured by ToyotaMaterial Incorporated of Japan), ceramics and composites thereof such ascalcium phosphate (e.g., SKELITE™ manufactured by Biologix Inc.),thermoplastics such as polyaryletherketone (PAEK) includingpolyetheretherketone (PEEK), polyetherketoneketone (PEKK) andpolyetherketone (PEK), carbon-PEEK composites, PEEK-BaSO4 polymericrubbers, polyethylene terephthalate (PET), fabric, silicone,polyurethane, silicone-polyurethane copolymers, polymeric rubbers,polyolefin rubbers, hydrogels, semi-rigid and rigid materials,elastomers, rubbers, thermoplastic elastomers, thermoset elastomers,elastomeric composites, rigid polymers including polyphenylene,polyamide, polyimide, polyetherimide, polyethylene, epoxy, partiallyresorbable materials, such as, for example, composites of metals andcalcium-housing based ceramics, composites of PEEK and calcium housingbased ceramics, composites of PEEK with resorbable polymers, totallyresorbable materials, such as, for example, calcium housing basedceramics such as calcium phosphate, tri-calcium phosphate (TCP),hydroxyapatite (HA)-TCP, calcium sulfate, or other resorbable polymerssuch as polyaetide, polyglycolide, polytyrosine carbonate,polycaroplaetohe and their combinations.

The housing of the device can comprise acrylobutadiene styrene (ABS),polypropylene (PP), polystyrene (PS), polycarbonate (PC), polysulfone(PS), polyphenyl sulfone (PPSU), polymethyl methacrylate (acrylic)(PMMA), polyethylene (PE), ultra high molecular weight polyethylene(UHMWPE), lower density polyethylene (LPDE), polyamide (PA), liquidcrystal polymer (LCP), polyaryl amide (PARA), polyphenyl sufide (PPS),polyether etherketone (PEEK), polyvinyl chloride (PVC), polyethyleneterephthalate (PET), polytetra flouroethylene (PTFE),polyaryletherketone (PAEK), polyphenyl sulfone (PPSU), or a combinationthereof. In some embodiments, a device disclosed herein can comprisepolypropylene, polycarbonate, glass filled polycarbonate, a lowpermeability copolyester (e.g. Eastman MN211), polyisoprene rubber,and/or TPE injection moldable seals.

Various components of the device can have material composites, includingone or more of the above materials, to achieve various desiredcharacteristics such as strength, rigidity, elasticity, compliance,biomechanical performance, durability and/or radiolucency preference.One or more of the components of the device can comprise antimicrobialand/or antiseptic materials. The components of the device, individuallyor collectively, can also be fabricated from a heterogeneous materialsuch as a combination of two or more of the above-described materials.The components of the device can be monolithically formed or integrallyconnected.

The device can be ergonomically designed such that a subject or user isable to hold the device comfortably with one hand or both hands. Thedevice can have a compact form factor that makes it highly portable(e.g. easy to be carried around in a user's bag or purse). Exemplarydimensions (e.g. length, width and height) of the device can be given asfollows. In some embodiments, the length is about 1.5 inches, about 2.0inches, about 2.5 inches, about 3.0 inches, or about 3.5 inches. Thelength can be between about 2.0 inches and about 3.0 inches. The lengthcan be between about 1.5 inches and about 3.5 inches. In someembodiments, the width is about 1.25 inches, about 1.5 inches, about1.75 inches, about 2.0 inches, or about 2.25 inches. The width can bebetween about 1.5 inches and about 2.0 inches. The width can be betweenabout 1.25 inches and about 2.25 inches. In some embodiments, the heightis about 1.25 inches, about 1.5 inches, about 1.65 inches, about 2.0inches, or about 2.25 inches. The height can be between about 1.5 inchesand about 2.0 inches. The height can be between about 1.25 inches andabout 2.25 inches. The length by width by height can be about 2.5 inchesby about 1.75 inches by about 1.65 inches.

FIG. 3A shows a side sectional view of the device 100 prior to insertionof the cartridge assembly 180 into the device, and FIG. 3B shows acorresponding top view. FIG. 4A shows a side view of the device with thecartridge assembly inserted therein, and FIG. 4B shows a correspondingtop sectional view. Various features of the device 100 and the cartridgeassembly 180 are next described in detail with reference to the abovefigures and other relevant figures.

A. Recess for Skin Suction

Referring to FIGS. 1B and 3A, the housing base 102 of the device caninclude the recess 136. The recess can be provided on a portion (e.g.bottom surface) of the housing base. The recess can be formed as asunken cavity or trench on the housing base. In some cases, the recesscan be formed as a molded extrusion into the housing base. The recesscan be shaped like a cup and configured to provide a skin “cupping”effect with aid of vacuum pressure. The recess can be sized and/orshaped to receive a portion of a surface, e.g., subject's skin therein,and to permit the surface, e.g., skin to substantially conform to therecess under application of vacuum pressure. A surface of the recess canbe substantially in contact with the skin drawn into the recess. A gapbetween the skin and the recess can be negligible when the skin is drawninto the recess. The recess can serve as a suction cavity for drawingthe skin therein and for increasing capillary pressure differential. Therecess can be configured having a size and/or shape that enables anincreased volume of blood to be accumulated in the skin drawn into therecess. The increased volume of the fluid sample can depend in part on avolume and/or surface area of the skin that is drawn into the recess.

In some alternative embodiments, the device can be configured to drawother types of objects (e.g. objects that are not skin or skin surfaces)into the recess under vacuum, and to further draw a fluid sample fromthose objects. Examples of those other types of objects can includesponges, clothes, fabrics, paper, porous materials, organic produce suchas fruits or vegetables, or any solid materials that are holding (orcapable of holding) fluid samples therein or thereon. Additionalnon-limiting examples of biological samples suitable for use with thedevices of the disclosure can include sweat, tears, urine, saliva,feces, vaginal secretions, semen, interstitial fluid, mucus, sebum,crevicular fluid, aqueous humour, vitreous humour, bile, breast milk,cerebrospinal fluid, cerumen, enolymph, perilymph, gastric juice,peritoneal fluid, vomit, and the like. In some embodiments, a fluidsample can be a solid sample that has been modified with a liquidmedium. In some instances, a biological sample can be obtained from asubject in a hospital, laboratory, clinical or medical laboratory.

The recess can be configured to maintain contact with a skin surfacearea of the subject under vacuum pressure, prior to and as blood isbeing collected from penetrated skin of the subject. In someembodiments, the skin surface area of the subject in contact with therecess can be at least 3 cm², 4 cm², 5 cm², 6 cm², 7 cm², 8 cm², 9 cm²,or 10 cm², or any value therebetween. In some preferred embodiments, atleast 5 cm² of the skin surface area of the subject can be in fullcontact with the surface of the recess when the skin is drawn into therecess under vacuum pressure. In some embodiments, the volume of theskin enclosed within the recess can be at least about 1.0 cm³, 1.1 cm³,1.3 cm³, 1.4 cm³, 1.4 cm³, 1.5 cm³, 1.6 cm³, 1.7 cm³, 1.8 cm³, 1.9 cm³,2.0 cm³, 2.1 cm³, 2.2 cm³, 2.3 cm³, 2.4 cm³, 2.5 cm³, 2.6 cm³, 2.8 cm³,2.9 cm³, 3.0 cm³, or any value therebetween. In some embodiments, atleast 1.8 cm³ of the subject's skin can be enclosed within the recesswhen the skin is drawn into the recess under vacuum pressure. In someembodiments, the volume of the enclosed within the recess can besubstantially the same as an inner volume of the recess.

Optionally in any of the embodiments disclosed herein, the housing baseof the device can have more than one recess, e.g. 2, 3, 4, 5, 6, 7, 8,9, 10 or more recesses. The recesses can be connected to one another,for example by one or more channels. Alternatively, the recesses neednot be connected to one another. The recesses can be in fluidiccommunication with one or more of the vacuum chambers and depositionchambers described elsewhere herein. The plurality of recesses can beconfigured to permit suction to occur on multiple portions of a surface(e.g. skin surface). In some cases, the plurality of recesses can enableblood to be drawn from different portions of a user's skin (that isdrawn into the plurality of recesses).

The recess can be formed having any shape, design, depth, surface area,and/or size. The recess can have any convenient shape, such as a curvedshape, hemispherical, spherical cap, square, circle, cuboid,trapezoidal, disc, etc. The recess can be symmetrical, for example ahemisphere. Alternatively, the recess can have an irregular shape andneed not be symmetrical. The recess can have rounded corners or edges.Additional examples of possible shapes or designs include but are notlimited to: mathematical shapes, two-dimensional geometric shapes,multi-dimensional geometric shapes, curves, polygons, polyhedral,polytopes, minimal surfaces, ruled surfaces, non-orientable surfaces,quadrics, pseudospherical surfaces, algebraic surfaces, riemannsurfaces, geometric shapes, and so forth. Optionally in any of theembodiments disclosed herein, the recess can have a substantiallycircular or elliptical shape. The surface of the recess can be smooth.In some embodiments, the recess can be configured to have a shape and/orsize that can reduce or eliminate bruising on the skin when the skin isdrawn into the recess by vacuum pressure. Optionally, the surface of therecess can take on a variety of alternative surface configurations. Forexample, in some cases, the surface of the recess can contain raised ordepressed regions.

Referring to FIG. 1B, the recess can comprise a concave cavity. Theconcave cavity can enclose an interior volume of at least about 1.0 cm³,1.1 cm³, 1.3 cm³, 1.4 cm³, 1.4 cm³, 1.5 cm³, 1.6 cm³, 1.7 cm³, 1.8 cm³,1.9 cm³, 2.0 cm³, 2.1 cm³, 2.2 cm³, 2.3 cm³, 2.4 cm³, 2.5 cm³, 2.6 cm³,2.8 cm³, 2.9 cm³, 3.0 cm³, or any value therebetween. In someembodiments, the concave cavity can preferably enclose an interiorvolume of about 1.85 cm³.

The recess can have a depth ranging from about 2 mm to about 30 mm, orpreferably at least deep enough such that a skin portion of the subjectis drawn into and completely fills the recess under vacuum pressure. Thedepth can be a height of the recess. The depth can be measured relativeto an innermost portion of the recess. In some other embodiments, therecess can have a depth that is less than 2 mm or greater than 10 mm.

The recess can have a rigid surface (e.g. a rigid concave surface) thatdoes not deform when skin of a subject is drawn into the recess undervacuum pressure. Alternatively, the recess can have a flexible surface(e.g. a flexible concave surface). For example, the bottom of the recesscan include an elastic material such as an elastomer. The elasticmaterial can be configured to conform to the skin when the skin is drawninto the recess. The elastic material can compress or press against theskin when the skin is drawn into the recess. The compression can help toimprove the contact area between the skin and the recess. Increasedcontact area can allow the skin to completely fill the recess withreduced gaps or creases inbetween. This can help to ensure that the skinis sufficiently taut (under tension) prior to penetration of the skinfor blood collection. Holding the skin taut can enable deeper cuts to bemade in the skin. Furthermore, holding the skin taut can also hold thecuts open better compared to loose skin.

As shown in FIGS. 1B and 3A, the recess can be in the shape of aspherical cap. The spherical cap can be, for example a hemisphere orpart of a hemisphere. In some embodiments, a housing base diameter ofthe spherical cap can range from about 10 mm to about 60 mm, preferablyabout 25 mm. A height of the spherical cap can range from about 2 mm toabout 30 mm, preferably about 6 mm. A volume of a hemisphere formed bythe concave surface can be equivalent to, or about half, or about aquarter, of a volume of a vacuum chamber in the device.

Referring to FIGS. 1B and 3A, the recess can include the opening 140.The opening can be located at an innermost portion of the recess. Forexample, the opening can be located at an apex of the spherical-shapedrecess. The opening can be formed having any shape and/or size. In someembodiments, the opening can have a substantially circular or ellipticalshape. In some cases, the recess can have more than one opening, e.g.,1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 25, 50, 100, 1000, or more openings. Oneor more of the openings can be in fluidic communication with a vacuumsource and/or an enclosure holding one or more piercing elements. Insome cases, one or more openings, e.g., connected to a vacuum source,can be found throughout the surface of the recess, or at least 10%, 25%,or 50% of the surface of the recess. Optionally in any of theembodiments disclosed herein, a plurality of openings can be distributedacross the surface of the recess, for example in a manner similar to ashowerhead. A vacuum can be applied via the plurality of openings todraw a subject's skin into the recess. In some cases, one or more of theplurality of the openings can be further configured to permit one ormore piercing elements to extend and retract therethrough, and to piercethe skin that is drawn into the recess.

The opening 140 can provide access to/from the lumen 142. The device caninclude one or more piercing elements that are configured to extendthrough the lumen and out of the opening into the recess, to penetrateskin that is drawn into the recess under vacuum pressure. Thepenetration of the skin can permit blood to be drawn from the subject,e.g., as described in detail elsewhere herein. The lumen can include twoor more ports. For example, the lumen can include a first port 144leading to the deposition chamber 126 located in the housing base, and asecond port 150 leading to an enclosure 156 located in the housingcover. A piercing module 154 comprising one or more piercing elements158 can be provided in the enclosure 156.

A size of the recess 136 can be substantially greater than a size of theopening 140. For example, a size of the recess can be at least twice asize of the opening. In some embodiments, the size (e.g. diameter) ofthe opening can range from about 1.5 mm to about 6 mm, and the size(e.g. base diameter or width) of the recess can range from about 10 mmto about 60 mm. In some preferred embodiments, a diameter of the openingcan be about 5 mm, and a base diameter of the recess can be about 25 mm.

In some embodiments, a ratio of the size (e.g. diameter) of the openingto the size (e.g. base diameter) of the recess can be about 1:2, about1:3, about 1:4, about 1:5, about 1:6, about 1:7, about 1:8, about 1:9,about 1:10, about 1:20, about 1:25, about 1:50, or about 1:100, or anyratios therebetween. In some embodiments, a ratio of the size (e.g.diameter) of the opening to the size (e.g. base diameter) of the recesscan be about 1:2 to about 1:10, or from about 1:5 to about 1:50, or fromabout 1:10 to about 1:100. The aforementioned ratio can be also lessthan about 1:2, 1:3, 1:4, 1:5, 1:10, 1:15, 1:20; 1:25; 1:30; 1:50, or1:100. In some embodiments, the ratio of the size (e.g. diameter) of theopening to the size (e.g. base diameter) of the recess can be preferablyat least about 1:5.

A surface area of the recess 136 can be substantially greater than anarea of the opening 140. The surface area of the recess can beassociated with the interior of the recess (excluding the opening), andcan be measured across a 3D (e.g. a concave hemispherical) plane. Thearea of the opening can be measured across a substantially 2D orquasi-2D plane defined by the opening. In some embodiments, the surfacearea of the recess can be at least five times, six times, seven times,eight times, nine times, ten times, or twenty times the area of theopening. In some embodiments, the surface area of the recess can rangefrom about 75 mm² to about 2900 mm², and the area of the opening canrange from about 1.5 mm² to about 30 mm². In some embodiments, the areaof the opening can preferably be about 0.2 cm², and the surface area ofthe recess can preferably be about 5.2 cm².

In some embodiments, an area of the skin directly under the opening 140can be at least 1.5 times smaller than a total area of the skin drawninto the recess 136. In some embodiments, the area of the skin directlyunder the opening can be preferably at least 5 times smaller than thetotal area of the skin drawn into the recess.

Referring to FIG. 1B, the planar portion 132 of the housing base can beconfigured to be placed onto the skin (e.g., on the upper arm) of thesubject. The planar portion can be provided surrounding the recess. Anadhesive (not shown) can be placed on the planar portion of the housingbase. The adhesive can create an airtight hermetic seal on the skin thatprevents air from the ambient environment from entering the recess afterthe device is placed onto the subject's skin. The seal can also preventfluids (e.g., blood, gas, etc.) from escaping out of the recess into theambient environment after the device is placed onto the subject's skin.An appropriate biocompatible adhesive material or gasket material can beplaced on the planar portion on the housing base, to promote adhesion ofthe device onto the subject's skin for improved contact. Any suitableadhesive can be used. The adhesive can be a hydrogel, an acrylic, apolyurethane gel, a hydrocolloid, or a silicone gel.

The adhesive can be a hydrogel. Optionally in any of the embodimentsdisclosed herein, the hydrogel can comprise a synthetic polymer, anatural polymer, a derivative thereof, or a combination thereof.Examples of synthetic polymers include, but are not limited topoly(acrylic acid), poly(vinyl alcohol) (PVA), poly(vinyl pyrrolidone)(PVP), poly (ethylene glycol) (PEG), and polyacrylamide. Examples ofnatural polymers include, but are not limited to alginate, cellulose,chitin, chitosan, dextran, hyaluronic acid, pectin, starch, xanthan gum,collagen, silk, keratin, elastin, resilin, gelatin, and agar. Thehydrogel can comprise a derivatized polyacrylamide polymer.

In some embodiments, the adhesive can be a 3-layer laminate comprisingof (1) hydrogel for applying to the skin side), (2) Tyvek™, and (3) asecondary adhesive for bonding to the planar portion of the housing baseof the device.

In some embodiments, the adhesive can be pre-attached to the planarportion on the housing base of the device 100. The device can comprise aprotective film or backing covering the adhesive on the planar portion.The protective film can be removed prior to use of the device andplacement of the device on the subject's skin. In another embodiment, anadhesive in the form of a gel, a hydrogel, a paste, or a cream can beapplied to skin of the subject or to the planar portion on the housingbase of the device, prior to placement of the device on the subject'sskin. The adhesive can then be placed in contact with the subject's skinfor a predetermined amount of time (e.g., on the order of severalseconds to several minutes) in order to form an adhesion layer betweenthe skin and device. The adhesive can be a pressure-sensitive adhesiveor a heat-sensitive adhesive. In some embodiments, the adhesive can behypoallergenic.

In some embodiments, the adhesive can be a peelable adhesive, and canhave a shape and size corresponding to the planar portion on the housingbase of the device. In the example shown in FIG. 1B, the planar portionon the housing base can be in the shape of an annular ring, although anyshape can be contemplated. Accordingly, the peelable adhesive can beprovided as an annular ring corresponding to the planar portion on thehousing base.

In some embodiments, a fillet 138 can be provided at an interfacebetween the planar portion and the recess. For example, the fillet 138can extend continuously along a periphery of the recess adjoining theplanar portion of the housing base. The fillet can be configured havinga radius or curvature that can help to improve vacuum suction to theskin and to reduce vacuum leak. For example, the fillet of the recesscan conform to and be substantially in contact with the skin of thesubject when the skin is drawn into the recess. In some embodiments, afillet 139 can be provided along the periphery of the opening, forexample as shown in FIGS. 1B and 3A. The use of fillets can alsoeliminate sharp edges and reduce unwanted cuts or bruises to the skinwhen the skin is drawn into the recess under vacuum pressure.

Optionally in any of the embodiments disclosed herein, the recess can becoated or sprayed with a copper, silver, titanium or other metal,coating, or any other antimicrobial material, anti-viral material,surfactants or agents that are designed to reduce microorganisms,disease, virus, cellular, bacteria, or airborne or surface particulatesfrom clinging onto the surface and/or edges of the recess. Optionally inany of the embodiments disclosed herein, one or more walls of the recesscan be impregnated with an antimicrobial material. For example, theantimicrobial material can be integrally formed with the recess of thehousing to help control the bacterial level present on or within therecess.

B. Vacuum Chamber and Deposition Chamber

The device can include a vacuum chamber 112 and a deposition chamber126, for example as shown in FIGS. 2A, 2C, 3A and 4B. The vacuum chamberand the deposition chamber can be provided in the housing (e.g.integrated into the housing base). Optionally, the vacuum chamber andthe deposition chamber can be operably coupled to a separately providedhousing. The vacuum chamber can be configured to be in fluidiccommunication with the recess and the deposition chamber. The vacuumchamber and the deposition chamber can be part of the housing base. Thevacuum chamber and the deposition chamber can be located in differentsections (e.g. compartments) of the housing base, and provided havingvarious shapes or configurations. For example, in some embodiments, thevacuum chamber can be shaped like a horse-shoe surrounding thedeposition chamber, as shown in FIGS. 2A and 4B. The vacuum chamber andthe deposition chamber can be separated by one or more walls 125. Thewalls can be substantially impermeable to fluids (e.g. gases andliquids) and can prevent leaks between the chambers. The walls can bemade materials having very low permeability values. For example,polypropylene can have a permeability coefficient of 9×10⁻¹¹ (cm³cm)/(sec·cm²·cm·Hg) to oxygen, and 4.5×10⁻¹¹ (cm³ cm)/(sec·cm²·cm·Hg) toair. As an example, PETG can have a permeability coefficient of1.5×10⁻¹¹ (cm³ cm)/(sec·cm²·cm·Hg) to oxygen, and 7.5×10⁻¹² (cm³cm)/(sec·cm²·cm·Hg) to air. In some alternative cases, the vacuumchamber and the deposition chamber need not be separated, e.g., bywalls. For example, the vacuum chamber and the deposition chamber can bethe same chamber in a device as packaged. The combined vacuum chamberand the deposition chamber can be a monolithic chamber. A chamber canhave more than one function or purpose, for example 2, 3, 4, 5, 6, 7, 8,9, 10 or more functions or purposes. For example, in some cases, avacuum chamber can also serve the function of a deposition chamber.Likewise, in some cases, a deposition chamber can also serve thefunction of a vacuum chamber.

The deposition chamber can be interchangeably referred to as a cartridgechamber, since the deposition chamber can be configured to receive acartridge assembly 180 therein. Blood can be collected from the subject,and transported from the recess into the deposition chamber forcollection and storage onto a cartridge 182. In some cases, the devicecomprises more than one vacuum chamber, e.g., 2, 3, 4, 5, 6, 7, 8, 9,10, or more vacuum chambers (each vacuum chamber can be connected to adifferent recess or the same recess), and/or more than one depositionchamber, e.g., 2, 3, 4, 5, 6, 7, 8, 9, 10, or more deposition chambers(each deposition chamber can be connected to the same vacuum chamber ora different vacuum chamber). Any number of vacuum chambers and/ordeposition chambers can be contemplated for depending on designapplications and needs.

The housing base can include a lid 124 that covers and hermeticallyseals the vacuum chamber. The lid can serve as a vacuum chamber lid. Thelid can also cover the deposition chamber or a portion thereof. Thevacuum chamber can be an evacuated chamber, and can be referred tointerchangeably as such. Referring to FIG. 4B, the vacuum chamber caninclude a self-sealing septum 122 through which air can be drawn out ofthe vacuum chamber. A vacuum state can be generated in the vacuumchamber, for example by inserting a distal end of a syringe through theseptum 122, and using the syringe to draw air out of the vacuum chamber.The distal end of the syringe can comprise a needle that is insertedthrough the septum into the vacuum chamber. The septum can be made ofany appropriate airtight flexible or elastomeric material. In someembodiments, the septum can be made of polyisoprene. The septum can bein a naturally sealed state, and can revert to its sealed state when theneedle is removed from the septum.

In some other embodiments, a mechanical device such as a vacuum pump canbe used to evacuate the vacuum chamber (e.g., before or afterpackaging). The mechanical device can include components such aspistons, motors, blowers, pressure regulators, and the like. In somecases, non-mechanical means, such as chemicals or other reactants, canbe introduced to the vacuum chamber and can undergo reaction to decreasepressure within the vacuum chamber (e.g., create a vacuum state).

The housing base can include a separation interface 120 that separatesthe vacuum chamber from the deposition chamber. The separation interfacecan be, for example a foil. In some embodiments, the separationinterface can be a multi-layer foil laminate. The separation interfacecan include any materials or means that can serve as a fluidic barrierbetween the vacuum chamber and the deposition chamber. The separationinterface can be “opened” to enable fluidic communication between thevacuum chamber and the deposition chamber. Other non-limiting examplesof a separation interface include diaphragms, caps, seals, lids,membranes, valves, and the like. The separation interface can be bondedto the housing base using any of the attachment means described herein.The separation interface can include any suitable polymer or compositematerial that can be pierced by a sharp object. The separation interfacecan be impermeable or semipermeable to gas or liquids. For example,suitable materials for use in the separation interface can includepolymer thin films, polyethylene, latex, etc.

The separation interface, e.g., foil, can help to maintain the vacuumpressure in the vacuum chamber, and the pressure difference between thevacuum chamber and the deposition chamber. Piercing the separationinterface, e.g., foil, can result in pressure equalization between thevacuum chamber and the deposition chamber, and create a pressuredifferential (negative pressure) that (1) draws the skin into the recessand (2) further draws blood from skin of the subject after the skin hasbeen penetrated. In some embodiments, a vacuum pressure of at leastabout −1 psig to −2 psig is provided, in order to draw the surface,e.g., skin into the recess and completely fill the recess. In someembodiments, the skin is drawn into the recess by the vacuum andcompletely fills the recess in less than 2 seconds, preferably less than1 second. In some embodiments, the skin is drawn into the recess by thevacuum and completely fills the recess in no more than 5 seconds.

In some cases, the vacuum chamber and the deposition chamber need not beseparated, i.e., the vacuum chamber and the deposition chamber can bethe same chamber, or can collectively constitute a same chamber. Inthose cases, the combined vacuum chamber/deposition chamber can beseparated from an opening of the recess by a separation interface, e.g.,foil. As an example, the separation interface can be provided at orproximal to the opening of the recess, and can be used to establishfluidic communication between the recess and the combined vacuumchamber/deposition chamber.

As previously described, the recess of the device can be configuredhaving a size and/or shape that enables higher average flowrate, and anincreased volume of blood to be accumulated and collected. Thecollection flowrate can be dependent on the shape and/or size of therecess. For example, the recess shown in FIG. 1B can aid in enhancingthe flowrate of blood collected from the subject.

The increased volume and flowrate of the blood collection can alsodepend on a starting or initial vacuum pressure of the vacuum chamber.The starting or initial vacuum pressure can correspond to the pressureof the vacuum chamber post evacuation. In some embodiments, the initialvacuum pressure of the vacuum chamber can range from about −4 psig toabout −15 psig, preferably about −8 psig to about −12 psig. In somepreferred embodiments, the initial vacuum pressure of the vacuum chambercan be about −12 psig. In some other embodiments, the initial vacuumpressure of the vacuum chamber can be less than −15 psig, for example−16 psig, −17 psig, −18 psig, −19 psig, −20 psig, −21 psig, −22 psig,−23 psig, −24 psig or lower.

The vacuum chamber can have a volume V1 ranging from about 3 cm³ toabout 30 cm³. The deposition chamber can have a volume V2 ranging fromabout 1 cm³ to about 20 cm³.

In some embodiments, the volume V1 of the vacuum chamber is preferablyabout 10 cm³′ and the volume V2 of the deposition chamber is preferablyabout 6 cm³.” The volumes of the vacuum chamber and the depositionchamber can be designed such that the pressure in both chambersequalizes to a desired value when the separation interface, e.g., foil,separating the two chambers is pierced. For example, the vacuum chambercan have an initial starting vacuum pressure of about −12 psig, and theratio of V1 to V2 can be configured such that the equalized pressure inboth chambers is about −4 psig after the foil is pierced. Any ratio ofV1:V2 can be contemplated, for example 1:1, 1:2, 1:3 and so forth.

In some embodiments, the increased volume of the blood in the skin drawninto the recess is at least about 20 μL, 30 μL, 40 μL, 50 μL, 60 μL, or70 μL prior to the penetration of the skin. Higher flowrates and bloodsample collection volumes can be achieved in part due to the increasedvolume of blood in the skin drawn into the recess, increased capillarypressure, and with aid of the vacuum pressure. In some embodiments, thedevice is capable of drawing blood from penetrated skin and collectingthe blood at a flowrate of at least about 30 μL/min. In someembodiments, the device can be capable of drawing blood from penetratedskin and collecting the blood at a flowrate of more than 600 μL/min.Generally, the device is capable of drawing blood from penetrated skinand collecting the blood at an average flowrate of at least about 100μL/min, 125 μL/min, 150 μL/min, or any values or ranges therebetween. Insome embodiments, the device can sustain the aforementioned averageflowrate(s) at least until a substantial amount of blood has beencollected (e.g. ranging from about 150 μL to about 1000 μL of blood, orin some cases more than 1 mL of blood). In some embodiments, the deviceis capable of collecting about 250 uL of fluid sample from the subjectin less than 1 min 45 secs. In some cases, the device is capable ofcollecting at least 175 uL to 300 uL of fluid sample from the subject inless than 2 mins. In some cases, the device is capable of collecting atleast 200 μL of fluid sample from the subject in less than 4 minutes.

In some other embodiments, the device 100 can be configured to collectsmaller amounts of blood (e.g. less than 150 uL, 140 uL, 130 uL, 120 uL,110 uL, 100 uL, 90 uL, 80 uL, 70 uL, 60 uL, 50 uL, 40 uL, 30 uL, or 25uL) of blood from a subject within a time window beginning from time ofincision or penetration of a skin portion of the subject. The timewindow can be less than 5 minutes, preferably less than 3 minutes. Insome embodiments, the time window can be under 2 minutes. In someembodiments, the time window can be under one minute.

In some embodiments, (1) the size and/or shape of the recess and/or (2)the vacuum pressure can be configured to achieve a minimum capillarypressure in the skin drawn into the recess. Similarly, (1) the sizeand/or shape of the recess and/or (2) the vacuum pressure can beconfigured to achieve a minimum tension in the skin drawn into therecess. As an example, the tension of the skin can be about 0.8lbs/force at a vacuum pressure of about −1 psig.

An area of skin under vacuum when the device is applied to the skin canbe about 100 to about 1000 mm², or about 100, 200, 300, 400, 500, 600,700, 800, or 900 mm². An area of skin under the opening can be about 0.1mm² to about 20 mm², or about 2, 4, 6, 8, 10, 12, 14, 16, 18, or 20 mm².An area of skin under vacuum when the device is applied to the skin canbe at least 100, 200, 300, 400, 500, 600, 700, 800, or 900 mm², or lessthan 100, 200, 300, 400, 500, 600, 700, 800, or 900 mm², or about 100 toabout 900 mm², or about 200 to 800 mm².

In some embodiments, an area of skin under vacuum is an area of skinencompassed by the area of the concave cavity at the housing base of thedevice. In some embodiments, an area of skin under vacuum is an areaskin under the opening. In some embodiments, an area of the skin underthe opening is at least 5 times smaller than an area of skin undervacuum when the device is applied to the skin. In some embodiments, anarea of skin under the opening is about 5, about 10, about 20, about 30,about 40, about 50, about 60, about 70, about 80, about 90, about 100times, about 200, about 300, about 400, about 500, about 600, about 700,about 800, about 900, about 1000, about 2000, about 3000, about 4000,about 5000, about 6000, about 7000, about 8000, about 9000, or about10,000 times smaller than an area of skin under the vacuum. An area ofskin under the opening can be less than 5, 10, 20, 30, 40, 50, 60, 70,80, 90, 100, 200, 300, 400, 500, 600, 700, 800, 900, 1000, 2000, 3000,4000, 5000, 6000, 7000, 8000, 9000, or 10000 times smaller than an areaof skin under the vacuum.

C. Piercing Module

The device can include a piercing module 154 for penetrating skin of thesubject when the skin is drawn into the recess under vacuum pressure. Insome alternative cases, the device need not comprise a piercing module.The piercing module 154 can be provided in an enclosure 156. Theenclosure can be located within the housing cover 152. The enclosure canbe provided as a separate component that is coupled to the housing cover(see, e.g. FIG. 26). FIG. 26 show a vertical axis Z-Z' extending throughhousing cover 152, lid 124 and housing base 110. FIG. 26 also shows anaxis A-A' extending through button 167 and enclosure 156. FIG. 26further shows an axis B-B' extending through button 115, depositionchamber 126, cartridge 182, and cartridge holder 190. The piercingmodule can include one or more piercing elements 158 supported by aholder 160, for example as shown in FIGS. 27A and 27B. The piercingelements can include lancets, lances, blades, needles, microneedles,surgical knives, sharps, rods, and the like. Any number of piercingelements (e.g., at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or more piercingelements) can be contemplated. In some embodiments, the piercingelements can preferably comprise two lancets.

The piercing elements can comprise tempered steel, high carbon steel, orstainless steel. Examples of stainless steel include, but are notlimited to 304 stainless steel, 316 stainless steel, 420 stainlesssteel, and 440 stainless steel. In some embodiments, the piercingelements can be coated with a surface finish. The surface finish canincrease lubricity during a skin cut. The surface finish can alsoimprove sharpness or penetration ability of the piercing elements. Insome embodiments, the surface finish can be a zirconium nitride coatingor a titanium nitride coating.

The piercing elements can be made of a biocompatible plastic or abiocompatible metal. The biocompatible plastic can include a number ofsuitable types of polymeric materials including, but not limited to,thermosets, elastomers, or other polymeric materials. Further, suitablebiocompatible metals can include, for example, stainless steel,titanium, etc. Additionally or optionally, the piercing elements can beformed from various composite materials. The piercing elements can bemanufactured using a number of suitable production processes. Forexample, the piercing elements can be fabricated using known metalprocessing techniques, such as casting or forging, or for the case ofpolymeric materials, any suitable polymer processing system can be used,including, for example, injection molding. A piercing element can have asharp, pointed end that can be used to pierce a user's skin in order tocollect blood.

The piercing module can further comprise one or more actuation elements(e.g., spring elements) for actuating the holder and moving the piercingelements. Other non-limiting examples of actuation elements can includemagnets, electromagnets, pneumatic actuators, hydraulic actuators,motors (e.g. brushless motors, direct current (DC) brush motors,rotational motors, servo motors, direct-drive rotational motors, DCtorque motors, linear solenoids stepper motors, ultrasonic motors,geared motors, speed-reduced motors, or piggybacked motor combinations),gears, cams, linear drives, belts, pulleys, conveyors, and the like.Non-limiting examples of spring elements can include a variety ofsuitable spring types, e.g., nested compression springs, bucklingcolumns, conical springs, variable-pitch springs, snap-rings, doubletorsion springs, wire forms, limited-travel extension springs,braided-wire springs, etc. Further, the actuation elements (e.g., springelements) can be made from any of a number of metals, plastics, orcomposite materials.

In some embodiments, the spring elements can include a deployment spring162 positioned to deploy the one or more piercing elements through theopening of the recess, to penetrate the skin of the subject. An exampleof a deployment spring is shown in FIG. 28A. In some embodiments, thedeployment spring can be configured to move and cause the piercingelements to penetrate the skin at speeds ranging from about 0.5 m/s toabout 1.5 m/s, preferably about 1 m/s, and with a force ranging fromabout 1.3N to about 18N. The deployment spring can be configured tocause the one or more piercing elements to penetrate the skin to depthsranging from about 0.5 mm to about 3 mm.

The spring elements can further include a retraction spring 164positioned to retract the one or more piercing elements through theopening back into the device, after the skin of the subject has beenpenetrated. An example of a retraction spring is shown in FIG. 28B. Theretraction spring can be configured to retract the piercing elementsfrom the skin of the subject at a speed of about 0.2 m/s. A spring-forceof the retraction spring can be less than a spring-rate of thedeployment spring. In some embodiments, the deployment spring can have aspring-rate of about 2625 N/m, and the retraction spring can have aspring-force of about 175 N/m.

A piercing element can have a length of about 1.0 mm to about 40.0 mm,or about 1.0 mm, about 1.5 mm, about 2.0 mm, about 4.0 mm, about 6.0 mm,about 8.0 mm, about 10.0 mm, about 15.0 mm, about 20.0 mm, about 25.0mm, about 30.0 mm, about 35.0 mm, about 40.0 mm; a width of about 0.01mm to about 3.0 mm, or about 0.01 mm, about 0.05 mm, about 0.1 mm, about0.5 mm, about 1.0 mm, about 1.5 mm, about 2.0 mm, about 2.5 mm, about3.0 mm. The length of a piercing element can be measured along alongitudinal direction, for example as shown by length l in FIG. 27A.

Each of the one or more piercing elements can be configured to piercethe skin of the subject to a depth of about 1.0 mm to about 25.0 mm, orabout 1.0 mm, 1.5 mm, 2.0 mm, 3.0 mm, 4.0 mm, 5.0 mm, about 6.0 mm,about 7.0 mm, about 8.0 mm, about 9.0 mm, about 10.0 mm, about 15.0 mm,about 20.0 mm or about 25 mm. In some embodiments, a penetration depthof the one or more piercing elements can be preferably about 2 mm intothe skin of the subject.

In some embodiments, the piercing elements can include lancets, and alength l of the lancet can be preferably less than about 13 mm. Thislength can be relatively shorter than currently commercially availablelancets, and the shorter length of the lancets in the embodimentsdescribed herein can help to reduce the form factor of the device, aswell as the type of spring and spring forces for actuating thoselancets. For example, a shorter spring with lower spring-rate is neededto actuate a shorter lancet, as compared to longer lancets which tend torequire longer springs and higher spring-rates. Shorter springs andlancets can help to reduce the size of the piercing module, which leadsto a corresponding reduction in the size of the housing cover and theoverall size of the device.

In some embodiments, two or more piercing elements can be supported bythe holder in a random configuration. For example, two or more piercingelements can have random orientations relative to each other. The two ormore piercing elements can comprise beveled edges that are randomlyoriented relative to each other. The beveled edges of the two or morepiercing elements can be non-symmetrical to each other. For example, thebeveled edges of the two or more piercing elements can be at an acute oroblique angle relative to each other. Accordingly, the two or morepiercing elements in the above configuration can be configured togenerate cuts on the skin that extend in different directions along theskin, and that are non-parallel to each other.

In some alternative embodiments, two or more piercing elements can besupported by the holder in a predefined configuration. The two or morepiercing elements can have predefined orientations relative to eachother. For example, the two or more piercing elements can comprisebeveled edges that are oriented relative to each other in a predefinedmanner. The beveled edges of the two or more piercing elements can besymmetrical to each other.

In some embodiments, the piercing elements can include two or morelancets. The lancets can have a same bevel angle, or different bevelangles. An example of a lancet and a bevel angle is shown in FIG. 27A.The bevel angle(s) can range from about 10 degrees to about 60 degrees.In some embodiments, the bevel angle of the lancets can be preferablyabout 42 degrees. The two or more lancets can have a same bevel length.Alternatively, the two or more lancets can have different bevel lengths.The bevel length of a lancet as described herein can refer to a lengthof the sharp beveled or slanted edge of the lancet, as shown by l′ inFIG. 27A. In some embodiments, the bevel length of a lancet can rangefrom about 1.6 mm to about 2.2 mm.

A method for penetrating the skin of a subject using the device 100 canbe provided as follows. The method can include (1) placing the deviceonto the skin of the subject, (2) drawing skin into the recess of thedevice using vacuum, (3) activating an actuation element (e.g., adeployment spring) and deploying the one or more piercing elementsthrough the opening in the device; (4) penetrating the skin of thesubject using the one or more piercing elements; and (5) using anotheractuation element (e.g., a retraction spring) to retract the one or morepiercing elements back into the device.

D. Vacuum Activator and Piercing Activator

The device can include a vacuum activator 114 configured to activate the(evacuated) vacuum chamber, which generates a vacuum pressure that candraw the skin into the recess and subsequently facilitate collection ofblood from the penetrated skin. The device can also include a piercingactivator 166 configured to activate the deployment spring, foractuating the piercing elements. The vacuum activator can be separatefrom the piercing activator. For example, the vacuum activator and thepiercing activator can be two separate discrete components of thedevice. In some alternative embodiments (not shown), the vacuumactivator and the piercing activator can be integrated together as asingle component that can be used to simultaneously or sequentiallyactivate the vacuum and the piercing elements.

The vacuum activator can include a first input interface, and thepiercing activator can include a second input interface. The first andsecond input interfaces can be located on different parts of thehousing. Examples of suitable input interfaces can include buttons,knobs, finger triggers, dials, touchscreens, keyboards, mice, orjoysticks. In some embodiments, at least one of the first inputinterface or the second input interface can comprise a button. Forexample, the vacuum activator can include a button 115 located on thehousing base 110, and the piercing activator can include a button 167located on the housing cover 152. In some embodiments, the vacuumactivator and the piercing activator can be located on a same side ofthe housing, and the buttons 115/167 can be ergonomically accessible bythe subject when the device is mounted onto an arm of the subject. Thebuttons can have distinct or different shapes and/or sizes, and can beergonomically located for ease of use (e.g. easy identification by theuser and well placed locations for simple activation).

In some alternative embodiments (not shown), at least one of the firstor second input interfaces can be remote from the housing of the device.For example, one or both of the first and second input interfaces can belocated on a user terminal (e.g. a mobile device or remote controller)that is connected with the device 100 via one or more wired or wirelesscommunication channels.

Examples of wireless communication channels can include Bluetooth®,WiFi, Near Field Communication (NFC), 3G, and/or 4G networks. Signalsfor activating the vacuum and/or the piercing elements can betransmitted remotely from the user terminal to the device 100 over theone or more communication channels.

In some embodiments, the vacuum activator can be activated first,followed by the piercing activator. In other words, vacuum pressure canbe activated prior to activation of the piercing elements. In certainembodiments, the piercing activator can be activated only after thevacuum activator and vacuum have been activated. For example, thepiercing activator can be initially in a locked state, and incapable ofactivating the one or more piercing elements prior to activation of thevacuum. The piercing activator can be unlocked only after the vacuumactivator has been activated. The above effect can be achieved byproviding a locking mechanism that couples the piercing activator to thevacuum activator. The locking mechanism can be configured such that thepiercing activator is initially in the locked state. The vacuumactivator can function as a key for unlocking the piercing activator,and the piercing activator can be simultaneously unlocked when thevacuum activator is activated. Referring to FIGS. 7A and 7B, the lockingmechanism can include a locking pin 169 coupled to the button 115 of thevacuum activator. Prior to use of the device for sample collection, thelocking pin can be engaged in a slot or hole 174 located on the button167 of the piercing activator, which prevents the button 167 from beingpressed down by a user. Accordingly, the piercing activator is incapableof being activated when the button 167 is in the locked position. Whenthe user presses the button 115, the locking pin 169 retracts in thedirection shown in FIG. 7B and disengages from the slot 174, thusunlocking the button 167. Pressing the button 115 also pierces the foil120 separating the vacuum chamber and the deposition chamber whichcauses the vacuum to be activated. Specifically, the chambers equalizeto a negative pressure which draws the subject's skin into the recess.The user can then press down the unlocked button 167 to activate thepiercing elements 158 for penetrating the subject's skin that is drawninto the recess.

In some embodiments, the piercing activator can be configured toactivate the one or more piercing elements after the skin is drawn intothe recess. The piercing activator can be configured to activate the oneor more piercing elements after the skin is drawn into the recess by thevacuum for a predetermined length of time. The predetermined length oftime can range, for example from about 1 second to about 60 seconds.

The vacuum activator can be configured to activate the vacuum bypiercing the foil, which establishes fluidic communication between thevacuum chamber, deposition chamber, and the recess, and introducesnegative pressure in the recess and the deposition chamber.

In some embodiments (not shown), the foil can be replaced by a valve,and the vacuum activator can be configured to open the valve toestablish the fluidic communication. A valve can be a flow control valvehaving a binary open and closed position. Alternatively, a flow controlvalve can be a proportional valve that can control the flow rate of theair that flows between the vacuum chamber and the deposition chamber.For example, a proportional valve can have a wide open configurationthat can permit a greater rate of flow than a partially openconfiguration that can permit a lesser rate of flow. Optionally,regulating, throttling, metering or needle valves can be used. Return ornon-return valves can be used. A valve can have any number of ports. Forexample, a two-port valve can be used. Alternatively, a three-port,four-port or other type of valve can be used in alternativeconfigurations. Any description herein of valves can apply to any othertype of flow control mechanism. The flow control mechanisms can be anytype of binary flow control mechanism (e.g., containing only an open andclosed position) or variable flow control mechanism (e.g., which caninclude degrees of open and closed positions).

In some embodiments, the vacuum activator can be located on the housingsuch that the button 115 is configured to be pressed in a firstdirection when the device is mounted onto the subject's arm. Thepiercing activator can be located on the housing such that the button167 is configured to be pressed in a second direction when the device ismounted onto the subject's arm. In some embodiments, the first directionand the second direction can be substantially the same. The firstdirection and the second direction can be substantially parallel to eachother. In some embodiments, the first direction and the second directioncan be substantially different, e.g. orthogonal or oblique to eachother.

In some embodiments, at least one of the first direction or the seconddirection does not extend toward the skin of the subject. For example,the second direction may not extend toward the skin of the subject. Atleast one of the first direction or the second direction can extendsubstantially parallel to the skin of the subject. In some embodiments,the first direction and the second direction can both extendsubstantially parallel to the skin of the subject. At least one of thefirst direction or the second direction can extend in a direction ofgravitational force. In some embodiments, the first direction and thesecond direction can both extend in the direction of gravitationalforce.

It is noted that pressing the button 167 of the piercing activator(which activates the piercing elements) in a direction away from theskin, for example downwards as opposed to against the skin, can beadvantageous in reducing the perception of fear and pain associated withskin penetration. By locating the piercing activator and the button 167on the housing in the configuration as shown, the overall userexperience with the device can be improved.

In some alternative embodiments (not shown), the vacuum activator can beconfigured to generate one or more visual, audio, tactile, and/ormessage signals to indicate the status of the vacuum to a user. Thesignals can indicate to the user, for example that (1) the vacuum hasbeen activated, (2) the pressure(s) within the different chamber(s), (3)the vacuum post internal pressure equalization, (4) that the piercingactivator is next ready for activation, and the like. The visual signalscan be generated using visible markers that are viewable to the nakedeye. A visible marker can include an image, shape, symbol, letter,number, bar code (e.g., 1D, 2D, or 3D barcode), quick response (QR)code, or any other type of visually distinguishable feature. A visiblemarker can include an arrangement or sequence of lights that can bedistinguishable from one another. For examples, lights of variousconfigurations can flash on or off. Any light source can be used,including but not limited to, light emitting diodes (LEDs), OLEDs,lasers, plasma, or any other type of light source. The visible markerscan be provided in black and white or in different colors. The visiblemarkers can be substantially flat, raised, indented, or have anytexture. In some instances, the visible markers can emit heat or otherIR spectrum radiation, UV radiation, radiation along the electromagneticspectrum.

The audio signals can include vibrations or sounds of differentfrequencies, pitches, harmonics, ranges, or patterns of sounds that canbe detected by the user. For example, the sounds can include words, ormusical tones. The vibrations/sounds can be discernible by the humanear. The vibrations/sounds can be used to indicate the status of thevacuum. For example, a first vibration/sound can be generated when thevacuum is properly activated, and a second vibration/sound differentfrom the first can be generated if the vacuum is improperly activated orbelow a minimum internal pressure differential.

In some alternative embodiments (not shown), the piercing activator canbe configured to generate one or more visual, audio, tactile, and/ormessage signals to a user. Such signals can be useful, for example inpreparing the user's state of mind for an impending penetration of theskin by one or more piercing elements. Such signals can be used todistract the user prior to, during and/after the cuts on the skin aremade. For example, lights and/or music emitted by the device can be usedto attract the user's attention, which can potentially help to reducethe pain level (or perception of pain) during and after the cuts aremade.

Optionally in any of the embodiments disclosed herein, the vacuumactivation can be semi-automatic or fully automatic. In someembodiments, the device need not require manual vacuum activation. Forexample, the device can be configured to automatically apply the vacuumupon sensing or detecting that the device has been placed on a surface(e.g., on a subject's skin), or that the recess of the device isproperly placed over the surface. Optionally in any of the embodimentsdisclosed herein, activation of the piercing elements can besemi-automatic or fully automatic. For example, the piercing elementscan be automatically activated to penetrate the surface (e.g., asubject's skin) upon sensing or detecting that the surface is drawn intothe recess of the device, and/or that the surface is in proximity to theopening (e.g., 140) of the recess. The above sensing or detection (forthe vacuum activation and/or piercing activation) can be enabled usingany variety or number of sensors. The sensors can be included with thedevice (e.g., onboard the device) or remote from the device.Non-limiting examples of sensors that can be used with any of theembodiments herein include proximity sensors, tactile sensors, acousticsensors, motion sensors, pressure sensors, interferometric sensors,inertial sensors, thermal sensors, image sensors, and the like. In somecases, if the vacuum activation and/or piercing activation is configuredto be semi-automatic or fully automatic, the buttons for the piercingactivator and/or piercing activator can be optionally included (oromitted) from the device.

E. Cartridge Assembly

As previously described, the deposition chamber of the device can alsofunction as a cartridge chamber, and these two terms can beinterchangeably used herein. The cartridge chamber can be configured toreceive a cartridge assembly. The cartridge assembly can include acartridge configured hold one or more matrices for storing a fluidsample (e.g., blood) thereon, and a cartridge holder. The cartridgeholder can be releasably coupled to the cartridge using for examplespring-clips. The cartridge assembly can be configured to releasablycouple to the device 100 used for collecting blood from the subject. Thecartridge holder can include a cartridge tab that is configured to bereleasably coupled to a distal end of the cartridge chamber. Thecartridge tab can be designed such that the subject or a user is able to(1) support the cartridge assembly by holding the cartridge tab, (2)couple the cartridge assembly to the device by pushing in the cartridgetab, and/or (3) decouple the cartridge assembly from the device bypulling the cartridge tab.

Referring to FIG. 3A, the cartridge can include a cartridge port 184that is configured to be releasably coupled to an output port 148 in thedeposition chamber 126. Fluidic communication can be established betweena channel 146 of the device and a channel 185 of the cartridge when theports 148 and 184 are coupled to each other. As shown in FIG. 3A, thechannel 146 can extend towards the port 144 which is adjacent to theopening 140 of the recess 136. Blood can be drawn from the penetratedskin of the subject, and transported through the channels 146 and 185into the cartridge with aid of vacuum, pressure differentials, andgravitational force.

The cartridge chamber can include cartridge guides 130 for guiding andholding the cartridge inside the cartridge chamber. The cartridgeassembly can be releasably coupled to the cartridge chamber via a quickrelease mechanism. A quick release coupling mechanism can enable a userto rapidly mechanically couple (attach) and/or decouple (remove) thecartridge assembly from the cartridge chamber with a short sequence ofsimple motions (e.g., rotating or twisting motions; sliding motions;depressing a button, switch, or plunger, etc.). For example, a quickrelease coupling mechanism can require no more than one, two, three, orfour user motions to perform a coupling and/or decoupling action. Insome instances, a quick release coupling mechanism can be coupled and/ordecoupled manually by a user without the use of tools. In someembodiments, the quick release coupling mechanism can include aluer-type fitting that mechanically engages with the cartridge when thecartridge assembly is inserted into the cartridge chamber.

The cartridge assembly can be coupled to the cartridge chamber prior tothe collection of blood from the subject, and decoupled from thecartridge chamber after blood from the subject has been collected intothe cartridge. The cartridge can include one or more matrices forcollecting, storing, and/or stabilizing the collected blood sample. Thematrices can be provided in strip form (as strips). A strip as usedherein can refer to a solid matrix that is sized to maximize bloodcollection volume while still fitting into commonly used containers(e.g., a 3 ml BD vacutainer, deep well plate or 2 ml Eppendorf tube). Amatrix as used herein can be interchangeably referred to herein as amatrix strip, a strip, a solid matrix, a solid matrix strip, and thelike. A solid matrix can be configured to meter out, collect andstabilize fixed volumes of blood or plasma (e.g., greater than 25 uL,greater than 50 uL, greater than 75 uL, greater than 100 uL, greaterthan 125 uL, greater than 150 uL, greater than 175 uL, greater than 200uL, or greater than 500 uL of blood or plasma). The cartridge assemblycan be configured to hold any number of matrices (e.g., 1, 2, 3, 4, 5,6, 7, 8, 9, 10 or more strips) and in various configurations.

The matrices can also enable lateral transport/flow of the blood.Non-limiting examples of the matrices can include absorbent paperstrips, or a membrane polymer such as nitrocellulose, polyvinylidenefluoride, nylon, Fusion 5™, or polyethersulfone. In some embodiments,the matrices can comprise cellulose housing based paper (e.g. Whatman™903 or 226 paper), paper treated with chemicals or reagents forstabilizing the sample or one or more components of the sample (e.g.,RNA stabilization matrix or Protein Stabilization Matrix). In someembodiments, the matrix comprises a cellulose filter paper. Any suitablecommercially available filter paper can be used. Examples ofcommercially available filter paper include, but are not limited to,filter paper from Whatman®, such as 903 sample collection cards and fasttransit analysis (FTA®) card. In some embodiments, the matrix cancomprise a nitrocellulose filter paper. In some embodiments, the matrixdoes not comprise glass fiber filter paper.

The collection of the fluid sample can be aided by the natural wickingor capillary action associated with the matrix, which can enhance andaccelerate the absorption or collection of the fluid sample onto thematrix. For a matrix having a surface area within the range of 100-300square millimeters, a standardized quantity of blood saturating thematrix can be within a range of about 50-100 uL. In some embodiments,the quantity of blood absorbed by each matrix is about 30 to about 100μL. In some embodiments, the quantity of blood absorbed by each matrixis about 67 to about 82 μL. In some embodiments, the quantity of bloodabsorbed by each matrix is 30 μL. In some embodiments, the quantity ofblood absorbed by each matrix is about 45 μL. In some embodiments, thequantity of blood absorbed by each matrix is about 60 μL. In someembodiments, the quantity of blood absorbed by each matrix is about 75μL. In some embodiments, the quantity of blood absorbed by each matrixis about 100 μL. In some cases, the matrices can be composed of amaterial comprising a plurality of capillary beds such that, whencontacted with a fluid sample, the fluid sample is transported laterallyacross the matrices. The fluid sample fluid can flow along a flow pathfrom a proximal end to a distal end of the matrices, for example bywicking or capillarity.

In some embodiments, two or more matrices are disposed in aconfiguration within the cartridge that permits the blood to wickbetween and flow along the matrices. The two or more matrices can bedisposed substantially parallel to each other. The two or more matricescan be separated by spacers. The spacers can be made of an appropriatebiocompatible material. Two or more spacers can be placed between twomatrices to form a channel through the blood can flow via capillaryaction and wicking. In the example of FIGS. 3A and 29, the two matrices186 can be separated by a pair of spacers 187. The spacers can bepositioned on opposing lengths of the matrices to form a channel 189through the blood can flow via capillary action and wicking. In someembodiments, the two or more matrices can be separated by a gap of about0.5 mm (i.e. the spacers can have a thickness of about 0.5 mm). Any gapsize may be contemplated. The spacers between the matrices can beadjustable and removable, depending on other relevant aspect (e.g. theneeds and application of the sample being collected, stability of theanalyte, rate of absorption requirements etc). The spacers can comprisea range of widths and coatings. Exemplary widths include widths in themillimeter to centimeter range (e.g., greater than 2 mm, greater than 4mm, greater than 6 mm, greater than 8 mm, greater than 10 mm, greaterthan 0.2 cm, greater than 0.4 cm etc.). In further embodiments, thespacers can be coated with materials including hydrophobic coatings,hydrophilic coatings, antimicrobial coatings, coatings that bind to oneor more components of a sample, coatings for binding to or inhibitingenzymes that can degrade or otherwise impact the quality of one or moreanalytes on the sample.

In some embodiments, at least one of the matrices is capable ofcollecting at least 60 uL of blood. In some cases, each of the two ormore matrices is capable of collecting at least 60 uL of blood. Thevolume of blood collected can depend on the number of the matrices inthe cartridge. For example, providing two matrices each with 60 uLholding capacity can yield a total blood sample volume of about 120 uL.

Referring to FIGS. 3A and 29, the cartridge assembly 180 can include oneor more absorbent pads 188 for holding excess fluid sample (e.g. excessblood flowing beyond the matrices). The absorbent pads can serve as awicking tail that can be used to absorb excess sample, and standardizeor meter the volume of blood deposited on the saturated matrices. Theabsorbent pads can be placed at a distal end of the channel 189 oppositeto the cartridge port 184, and can be placed in contact with endportions of the matrices 186. The absorbent pads can be supported orheld in place by the cartridge holder 190. For example, the absorbentpads can be placed in a slot in the cartridge holder. The absorbent padscan be configured to absorb excess sample overflow. Each absorbent padcan be capable of holding at least about 10 uL of excess fluid sample.In some cases, each absorbent pad can be capable of holding at leastabout 20 uL, 30 uL, 40 uL, 50 uL, 60 uL, 70 uL, 80 uL, 90 uL, 100 uL, ormore than 100 uL of excess fluid sample. The absorbent pads can be usedto enable controlled metering of the matrices. The absorbent pads andtheir ability to contain the blood beyond the saturation volume of thematrices can enable consistent volumes of blood on the matrices,independent of varying input volumes to the device and cartridge. Theabsorbent pads can be configured (e.g., composition adjusted) so thatthe absorbent pads can be used as a means to control the volume of thesample absorbed on the matrices.

The cartridge assembly can comprise self-metering capability which canbe advantageous for collecting a predefined volume of blood on thematrix strips for each individual, regardless of varying input volumesof blood flow to the cartridge for different individuals. The variationsin input blood volume can occur since capillary pressures and blood flowcan often vary from individual to individual (e.g., due to age, gender,health, etc.). The design of the cartridge assembly can ensure thatmatrix strips consistently contain a target blood volume independent ofthe volume of the blood that enters the cartridge (within or up to apredefined range). In the example of FIG. 29, the two matrix strips(e.g. 186) are in contact with one or more absorbent pads (e.g. 188) atthe ends opposite the inlet port (e.g. 184) of the cartridge. As bloodenters the cartridge via the port 184 during the draw, the matrix stripsgradually saturate and during this time, the volume contained within thestrips can increase (e.g. linearly) with the volume of blood that entersthe cartridge. In some embodiments, once the matrix strips are saturatedat ˜75 uL, the excess blood can wick onto the absorbent pad(s). By usingthe absorbent pads to absorb excess blood, the blood contained withinthe two matrix strips can be maintained at about 75 uL on each strip,even if (or as) the input volume of blood flowing into the cartridgeincreases beyond 150 uL. The volume of blood on the matrix strips can bemetered/maintained unless or until the absorbent pads saturate withblood. In some embodiments, any input volume of blood between ˜150 uLand 300 uL to the cartridge can still result in the same volume (˜75 uL)of blood contained on each of the two matrix strips, with aid of theabsorbent pad(s). In some embodiments, a range of blood volume collectedon the matrix strips can be increased or decreased, for example byadding one or more additional absorbent pads, increasing or decreasingthe strip size/saturation level, etc.

The collection of blood on the matrix strips can occur in phases. Forexample, during an initial phase, while the input volume of blood to thecartridge is between 0-150 uL, the two strips are filling but have notyet saturated, and the blood volume on each of the two strips increasesgradually from 0-75 uL. During a subsequent phase, as the input volumeof blood to the cartridge increases beyond 150 uL (e.g. 150 uL-300 uL),the strips are saturated at constant blood volume of ˜75 uL per strip,with excess blood flowing into the absorbent pads. The above-describedpassive metering mechanism can be advantageous in maintaining apredefined blood volume (e.g. 75 uL per strip) with varying blood inputvolumes within a target range.

It should be appreciated that the cartridge can include any number ofmatrix strips. The matrix strips can have the same saturation volumes orhave different saturation volumes. The cartridge can also include anynumber of absorbent pads. The number of absorbent pads may or may not bethe same as the number of matrix strips. The saturation volumes for theabsorbent pads can be the same or different. The cartridge can bedesigned such that the matrix strips and absorbent pads have aself-metering capability as described above. For example, the samplevolumes collected on the matrix strips can increase until the matrixstrips reach their saturation volumes. After the matrix strips aresaturated, any excess fluid is collected the absorbent pads.Accordingly, controlled well-defined volumes of the sample can becollected on the matrix strips, even though the input volume to thecartridge can and often exceeds the total saturation volumes of thematrix strips.

The use of the matrices with absorbent pads can facilitate accurate andprecise sample collection. Two or more matrices can be stacked orarranged in ways that facilitate blood collection, distribution,precision and reproducible volumes of sample or analyte per surface areaof each matrix. In some embodiments, the matrices can have differentcompositions or purposes. For example, a first matrix(es) can be used toseparate cells from a cell free component and collect the cell freecomponent on one matrix, and a second matrix(es) can be used collect rawunseparated sample. In some embodiments, the absorbent pads can be usedas or incorporated into an indicator or be visible through a viewingwindow (of a flow meter) to inform a user that the collection procedureis complete.

In some embodiments, a method for collecting a fluid sample (e.g.,blood) from a subject can be provided. The method can include: (1)releasably coupling the cartridge assembly to a device (e.g. device100); (2) placing the device adjacent to skin of the subject; (3)activating vacuum in the pre-evacuated vacuum chamber to draw the skininto a recess of the housing; (4) using one or more piercing elements ofthe device to penetrate the skin; (5) maintaining the device adjacent tothe skin for a sufficient amount of time to draw the fluid sample intothe device and collect the fluid sample into the cartridge; and (6)decoupling the cartridge from the device after a certain amount of thefluid sample has been collected in the cartridge.

In some embodiments, one or more of the matrices can be designed andfabricated on a substrate. The substrate can be rigid or flexible.Examples of suitable substrates can include silicon, glass, printedcircuit boards, polyurethane, polycarbonate, polyamide, polyimide, andthe like.

The cartridges described herein generally depict fluid samples stored onsolid matrices. However, this should not be taken to limit the devicesdisclosed herein. For example, the devices can include cartridges ormeans for collecting, treating, stabilizing and storing sample in eithera liquid or a solid state. In some embodiments (not shown), thecartridge can include a vessel for storing liquid sample. The vessel canbe used in conjunction with one or more matrices. Alternatively, thevessel can be used in place of matrices. Any number of vessels forstoring liquid sample can be contemplated.

In some embodiments, the device disclosed herein can have multiplevacuum chambers (e.g. 2, 3, 4, 5 or more vacuum chambers) and multiplepiercing modules (e.g., 2, 3, 4, 5 or more piercing modules). The devicecan be reusable and can be used to collect multiple samples in multiplecartridges. For example, a first vacuum chamber and a first piercingmodule can be activated to fill a first cartridge, a second vacuumchamber and a second piercing module can be activated to fill a secondcartridge, a third vacuum chamber and a third piercing module can beactivated to fill a third cartridge, and so forth. In some embodiments,a same vacuum chamber and piercing module can be used to fill aplurality of different cartridges, either within a same sample procedureor multiple procedures performed at different points in time.

F. Flow Meter

In some embodiments, the device can include a flow meter 170 on thehousing. The flow meter can be interchangeably referred to herein as ametering window (or metering windows). The flow meter can enable asubject or a user to monitor a progress of the fluid sample collection(e.g. blood sample collection) in real-time as the fluid sample iscollected into the cartridge. For example, the subject or user can relyon the flow meter to determine whether the fluid sample collection iscomplete or near completion. In some embodiments, the flow meter can beprovided on the housing base 110. For example, the flow meter can be apart of, or integrated into the lid 124 of the housing base. The flowmeter can be in proximity to the deposition chamber 126 (or cartridgechamber). The flow meter can be located directly above the depositionchamber (or cartridge chamber). The flow meter can be substantiallyaligned with the cartridge 182 when the cartridge assembly is insertedinto the cartridge chamber, for example as shown in FIGS. 3B, 4B, 20A,and 20B.

In some embodiments, the flow meter 170 can include a plurality ofwindows 172 disposed parallel to a longitudinal axis of the cartridgechamber. The plurality of windows can include three, four, five or morewindows. In the example of FIGS. 17B, 18B, and 19B, the flow meter 170can include windows 172-1, 172-2, 172-3, 172-4, and 172-5. The windowscan line up with the matrices 186 of the cartridge when the cartridgeassembly is inserted into the cartridge chamber. The windows can be madeof an optically transparent material that allows the subject or user tosee the underlying matrices in the cartridge. The fluid sample that iscollected on the matrices can be visible through the windows. The fluidsample and the matrices of the cartridge can have different colors,preferably highly contrasting colors to permit easy viewing of the flowof the fluid sample along the matrices. The color of the fluid sample(e.g. red color for blood) can sequentially fill each window as thefluid sample is being collected on the matrices in the cartridge. Eachwindow can be indicative of a known amount of fluid sample that iscollected. For example, in FIG. 17B, the window 172-1 can have a visiblecolor that indicates to the user that the matrices are about 20% filled.In FIG. 18B, the windows 172-1, 172-2, 172-3, and 172-4 can have avisible color that indicates to the user that the matrices are about 80%filled. In FIG. 19B, all of the windows 172-1, 172-2, 172-3, 172-4, and172-5 can have a visible color that indicates to the user that thematrices are 100% filled. Accordingly, the user is able to determinethat the sample collection is complete when the color of the fluidsample is visible in all of the windows.

FIGS. 17C, 18C, and 19C show a flow meter 175 in accordance with someother embodiments. The flow meter 175 can consist of a single window 176disposed parallel to a longitudinal axis of the cartridge chamber. Thesingle window can line up with the matrices 186 of the cartridge whenthe cartridge assembly is inserted into the cartridge chamber. Thesingle window can be made of an optically transparent material. Thefluid sample can be visible through the single window. The color of thefluid sample (e.g. red color for blood) can continuously fill the windowas the fluid sample is being collected in the cartridge. In someembodiments, the window can include one or more markers that indicate aknown amount of fluid sample that is collected. A user can be able todetermine that the fluid sample collection is complete when the color ofthe fluid sample is visible throughout the entire window.

In some alternative embodiments (not shown), the flow meter can includeone or more visible markers. The visible markers can replace the windowsof the flow meter, or can be used in conjunction with the meteringwindows. The visible markers can be viewable to the naked eye. A visiblemarker can include an image, shape, symbol, letter, number, bar code(e.g., 1D, 2D, or 3D barcode), quick response (QR) code, or any othertype of visually distinguishable feature. A visible marker can includean arrangement or sequence of lights that can be distinguishable fromone another. For examples, lights of various configurations can flash onor off. Any light source can be used, including but not limited to,light emitting diodes (LEDs), OLEDs, lasers, plasma, or any other typeof light source. The visible markers can be provided in black and whiteor in different colors. The visible markers can be substantially flat,raised, indented, or have any texture.

In some instances, the visible markers can emit heat or other IRspectrum radiation, UV radiation, radiation along the electromagneticspectrum. In another example, the device or flow meter can emitvibrations or sounds of different frequencies, pitches, harmonics,ranges, or patterns of sounds that can be detected by the user. Forexample, the sounds can include words, or musical tones. Thevibrations/sounds can be discernible by the human ear. Thevibrations/sounds can be used to indicate a progress of the fluid samplecollection process. For example, a first vibration/sound can begenerated when the fluid sample starts flowing onto the matrices, and asecond vibration/sound different from the first can be generated whenthe fluid sample has completely filled the matrices.

In some embodiments, the flow meter can be used to detect (e.g. enablethe subject or a user to view) a feature, colorimetric change, displayof a symbol, masking of a symbol, or other means of indicating theprogress of the fluid sample collection, and to indicate that the fluidsample collection has been completed.

In some embodiments, one or more graphical user interfaces (GUIs) can beprovided on the device. The GUIs can complement the use of the flowmeter. In some embodiments, the function of the flow meter can beincorporated into the GUIs. The GUIs can be rendered on a display screenon the device. A GUI is a type of interface that allows users tointeract with electronic devices through graphical icons and visualindicators such as secondary notation, as opposed to text-housing basedinterfaces, typed command labels or text navigation. The actions in aGUI can be performed through direct manipulation of the graphicalelements. In addition to computers, GUIs can be found in hand-helddevices such as MP3 players, portable media players, gaming devices andsmaller household, office and industry equipment. The GUIs can beprovided in a software, a software application, etc. The GUIs can beprovided through a mobile application. The GUIs can be rendered throughan application (e.g., via an application programming interface (API)executed on the device). The GUIs can allow a user to visually monitorthe progress of the sample collection. In some embodiments, the GUIs canallow a user to monitor levels of analytes of interest in the collectedsample.

In some embodiments, the device can be capable of transmitting data to aremote server or mobile devices. The data can include for example, userdetails/information, the date/time/location at which the sample iscollected from the subject, the amount/volume of sample collected, timetaken to complete the sample collection, maximum/minimum/averageflowrates during sample collection, position of the subject's arm duringsample collection, whether any errors or unexpected events occurredduring the sample collection, etc. In some cases, the data can betransmitted to a mobile device (e.g., a cell phone, a tablet), acomputer, a cloud application or any combination thereof. The data canbe transmitted by any means for transmitting data, including, but notlimited to, downloading the data from the system (e.g., USB, RS-232serial, or other industry standard communications protocol) and wirelesstransmission (e.g., Bluetooth®, ANT+, NFC, or other similar industrystandard). The information can be displayed as a report. The report canbe displayed on a screen of the device or a computer. The report can betransmitted to a healthcare provider or a caregiver. In some instances,the data can be downloaded to an electronic health record. Optionally,the data can comprise or be part of an electronic health record. Forexample, the data can be uploaded to an electronic health record of auser of the devices and methods described herein. In some cases, thedata can be transmitted to a mobile device and displayed for a user on amobile application.

G. Sample Collection

Next, exemplary methods of use of the devices herein for samplecollection are described with detail with reference to various figures.Referring to FIG. 5A, the device 100 having cartridge assembly 180 canbe placed on a subject's skin 104 (e.g. on the subject's upper arm). Thesubject's skin can be initially in a free state 105 (i.e. the skin isnot under tension or drawn into the recess by vacuum pressure). Theplanar portion 132 of the housing base 110 can be in contact with thesubject's skin, and attached to the skin with aid of an adhesive 134 asdescribed elsewhere herein. The device can be configured for use in theorientation as shown in FIG. 5A, with the channels 146 and 189 andmatrices 186 substantially aligned in the direction of gravity to aidsample flow.

FIG. 5B shows a schematic block diagram corresponding to FIG. 5A, anddepicts the different chambers and enclosure. Referring to FIG. 5A, thedevice 100 can include the (1) deposition chamber 126, (2) vacuumchamber 112, (3) enclosure 156 for holding the piercing module 154, and(4) a cavity 107 enclosed between the skin and the surface of therecess. The vacuum chamber and the deposition chamber can be separatedby the foil 120. The deposition chamber can be in fluidic communicationwith the cavity 107 and the enclosure 156 via channel 146. Prior tovacuum activation, the pressures within the deposition chamber 126(P_(dc)), enclosure 156 (P_(1a)), and channel 146 can be at atmosphericpressure (or ambient pressure). The pressure P_(vc) within the vacuumchamber 112 can be at its maintained pressure which is below atmosphericwhile the separation interface 120 is closed (e.g. when the foil isintact). In some embodiments, the pressure P_(vc) can be about −12 psigprior to breaking of the foil 120. The capillary blood pressure withinthe skin (P_(cap)) is at a pressure greater than atmospheric. In someembodiments (not shown), the separation interface 120 can include avalve which can be opened to establish fluidic communication between thevacuum chamber and the deposition chamber. In some cases, the foil canbe replaced by the valve, or used in conjunction with the valve.

Referring to FIGS. 6A and 6B, the vacuum in the vacuum chamber 112 canbe activated by opening the separation interface 120, for example bybreaking the foil (or in some cases, opening a valve). The vacuumactivator can comprise a sharp protrusion 116 coupled to the button 115.The vacuum can be activated by pressing the button 115 downwards (FIG.5A), which causes the protrusion 116 to break the foil (FIG. 6A).Subsequently, the pressure within the vacuum chamber, deposition,chamber, the enclosure and the internal channel equalizes at a pressure(P_(int)) which is below atmospheric but greater than the initialpressure of the vacuum chamber. In some embodiments, the equalizedpressure can be about −4 psig. This negative gauge pressure can draw theskin into the recess 136 and dras blood to that region within thecapillary beds. This action can result in an increase in the capillaryblood pressure within the skin which is now under tension within therecess.

As previously described, activation of the vacuum can release the lockon the button 167 of the piercing activator. Referring to FIGS. 8A and8B, when the button 167 is pressed downwards, the deployment spring 162(which can be initially in a compressed state) is deployed, and extendsthe piercing elements 158 towards the opening 140 to penetrate the skinat the opening. In some embodiments (not shown), the deployment springcan be initially in an uncompressed state, and compressed by one or moreactuating elements in preparation for deployment of the piercingelements. Referring to FIGS. 9A and 9B, the piercing elements areretracted from the skin by the retraction spring 164 after the skin hasbeen penetrated. The initial flow of blood is driven by the pressuredifferential between the capillary blood pressure (P_(cap)) and theinternal pressure of the device (P_(int)). As previously mentioned, theinternal pressure can be about −4 psig, and the capillary blood pressureis greater than atmospheric. Initially, a small amount of blood cantravel towards and into the enclosure 156 while blood can also enter thechannel 146 guiding it towards the deposition chamber 126.

Referring to FIGS. 10A, 10B, and 11, the flow of blood can quickly reacha “steady state.” As blood enters the device, the volume of the bloodpresent naturally causes the internal pressure to increase due to itsnegative gauge internal pressure. The volume V1a of the enclosure 156can be substantially smaller than the combined volume V_(dc+vc) of thedeposition chamber 126 and vacuum chamber 112. In some embodiments, aratio of V₁ a to V_(dc+vc) can be about 1:10. The enclosure 156 can havean internal pressure P_(int_1a), and the deposition chamber 126 andvacuum chamber 112 can collectively have an internal pressureP_(int_dc+vc). Due to the substantially smaller internal volume of theenclosure, the internal pressure P_(int_1a) within the enclosureincreases with the presence of blood much more rapidly than the internalpressure P_(int_dc+vc) within the deposition chamber and vacuum chamberwhich increases a very small amount. The internal pressure buildup inthe enclosure causes the flow of blood into the enclosure to slow orstop, while the blood continues to be drawn into the deposition chamberby the pressure differential between the internal pressures P_(int_1a)and P_(int_dc+vc) and the capillary blood pressure (P_(cap)). Blood flowtowards the deposition chamber can further be aided by gravitationalforce, and by capillary action along the channels 146 of the device andthe channel 189 of the cartridge. The blood flow can be further aided bywicking along the matrices 186 as the blood flows through the channel189 of the cartridge.

The preferential flow of blood towards the deposition chamber 126 allowsmore blood to be collected in the deposition chamber. Minimal bloodflowing into the enclosure 156 can also help to reduce wastage of blood,since blood in the enclosure is not collected and used. Accordingly, theabove-described device configurations can help to increase the flowrateand volume of blood collected in the deposition chamber.

FIGS. 11A through 16F are schematic block diagrams showing the sameoperating principles as the embodiments described in FIGS. 5A through10B. The schematic block diagrams are simplified generalized views ofthe device and the cartridge assembly, to show the change in pressuresbetween the chambers and the flow of fluids. As such, some of theelements can be omitted in the interest of clarity. Like referencenumerals refer to like elements throughout.

FIG. 11A shows a side sectional view of the device prior to insertion ofthe cartridge assembly, and FIG. 11B shows the corresponding front view.The cartridge assembly can include the matrices 186 and the cartridgetab 192. The device can include the (1) vacuum chamber 116, (2)deposition chamber 126, (3) recess 136, (4) enclosure 158 for thepiercing element 158, and (5) channel 146 leading to the depositionchamber. The deposition chamber and the vacuum chamber can be separatedby the foil 120. As shown in the FIG. 11B, the vacuum chamber cansurround the deposition chamber in a U-like shape, and the two chamberscan be separated by one or more walls 125. The pressures in the vacuumchamber, deposition chamber, and recess can be given by P_(v), P_(d),and P_(r), respectively. Initially, P_(d) and P_(r) can be atatmospheric pressure (P_(atm)). The pressure P_(v) within the vacuumchamber can be at a pre-evacuated vacuum pressure (P₀) which is belowatmospheric while the foil 120 is closed (i.e. the foil is intact).Initially, P₀ can be substantially less than P_(d). In some embodiments,P₀ can be about −12 psig. In some embodiments (not shown), the foil 120can be replaced by a valve which can be opened to establish fluidiccommunication between the vacuum chamber and the deposition chamber.

FIGS. 12A and 12 B show the cartridge assembly inserted into thedeposition chamber. Next, the device can be placed onto a subject's skin104, as shown in FIG. 13A. The skin can be initially in a free state 105(i.e. not under tension due to vacuum suction). A cavity 107 can beenclosed between the skin 104 and the surface of the recess 136. Theinitial pressures within the chambers and various compartments canremain the same since there is no fluidic communication causing anypressure changes.

Referring to FIGS. 14A and 14B, the vacuum in the vacuum chamber 112 canbe activated by breaking the foil 120 (or in some cases, opening avalve). The vacuum activator can comprise a sharp protrusion 116 coupledto the button 115. The vacuum can be activated by pressing the button115 downwards, which can causes the protrusion 116 to break the foil.Air from the deposition chamber 126, cavity 107, enclosure 156, andchannel 146 can be drawn into the vacuum chamber to equalize thepressures, as shown in FIGS. 14A and 14B. As a result, P_(d) and P_(r)will decrease while P_(v) increases. At the same time, the skin can bedrawn into the recess by the pressure differentials.

Referring to FIGS. 15A and 15B, the skin can be completely drawn intothe recess. The pressure P_(p) in the enclosure 156, P_(v) and P_(d),and the pressure in the channel 146 equalize at a pressure P₁, wherebyP₀<P₁<P_(atm). In some embodiments, P₁ can be about −4 psig. Thisnegative gauge pressure can draw and holds the skin in the recess 136,and draws blood to the skin region within the capillary beds. This canresult in an increase in the capillary blood pressure P_(c) within theskin which can now be under tension.

Next, referring to FIGS. 16A and 16B, the piercing element 158 can bedeployed and penetrate the skin at the opening 140 of the recess, andretracted from the skin as shown in FIG. 16C. The initial flow of bloodcan be driven by the pressure differential between P_(c) and P_(int),whereby P_(c)>P_(atm)>P₁. Initially, a small amount of blood can traveltowards and into the enclosure 156 while blood also enters the channel146 guiding it towards the deposition chamber 126, as shown in FIG. 16C.

The volume V_(1a) of the enclosure 156 can be substantially smaller thanthe combined volume V_(dc+vc) of the deposition chamber 126 and vacuumchamber 112. In some embodiments, a ratio of V_(1a) to V_(dc+vc) can beabout 1:10. As blood flows into the enclosure and towards the depositionchamber, the pressure P_(p) of the enclosure increases to P₂, and thepressures P_(d) and P_(v) of the deposition chamber and the vacuumchamber can increase to P₃. However, P₂ can be substantially greaterthan P₃ since V_(1a) can be substantially smaller than V_(dc+vc). Inother words, the pressure in the enclosure 156 increases much morerapidly than the pressure within the deposition chamber and vacuumchamber which increases by a very small amount. The internal pressurebuildup in the enclosure causes the flow of blood into the enclosure toslow or stop, while the blood continues to be drawn into the depositionchamber by the pressure differential between the internal pressuresP_(int_1a) and P_(int_dc+vc) and the capillary blood pressure P_(cap).Accordingly, the flow of blood reaches a “steady state” in which theblood is drawn only towards the deposition chamber. Blood flow towardsthe deposition chamber can be further aided by gravitational force g,and by capillary action c along the channels 146 of the device and thechannel 189 of the cartridge. The blood flow can be further aided bywicking w along the matrices 186 as the blood flows through the channel189 of the cartridge.

As previously described, the preferential flow of blood towards thedeposition chamber 126 can allow more blood to be collected in thedeposition chamber. Minimal blood flowing into the enclosure 156 canalso help to reduce wastage of blood, since in some cases blood in theenclosure is not collected and used. Accordingly, the above-describeddevice configurations can help to increase the flowrate and volume ofblood collected in the deposition chamber.

III. Packaging and Transportation of Cartridge Post Sample Collection

As previously described with reference to FIGS. 17A-19A, 17B-19B, and17C-19C, the use of flow meters on the device can allow a user tomonitor the progress of the sample collection, and to know when thesample collection has been completed. FIG. 20A shows a top view of thedevice with a completely filled cartridge, and FIG. 21A shows a top viewwith the filled cartridge removed from the device. The cartridgeassembly can be removed from the deposition chamber of the device bypulling the cartridge tab. The filled cartridge can be subsequentlypackaged and transported to an external facility for further processing.For example, the sample can be treated, stabilized and stored. In any ofthe embodiments described herein, the devices can be configured tocollect, treat, and store the sample. Samples drawn by the device can bestored in liquid or solid form. The sample can undergo optionaltreatment before being stored. Storage can occur on the device, off thedevice, or in a removable container, vessel, compartment, or cartridgewithin the device.

FIG. 22A shows a perspective view of a transportation sleeve 200 thatcan be used for packaging of a filled cartridge or samples within thecartridge. The sleeve can include a hollow interior for storing thefilled cartridge or samples during shipment/transportation. The sleevecan include an opening for receiving the cartridge. In some embodiments,the sleeve can include a cover 212 for covering the opening prior to useof the sleeve. The cover 212 can be, for example a peel foil that can beattached to the opening via an adhesive, and peeled off by a user priorto use of the sleeve. A dessicant (not shown) can be disposed within thesleeve, and used for keeping the samples dry. The peel foil can help toprotect the interior of the sleeve from moisture and contamination priorto use.

FIG. 22B shows a top view of the transportation sleeve and a filledcartridge assembly prior to its insertion into the sleeve. FIG. 22Cshows the filled cartridge assembly inserted into the transportationsleeve, with the cartridge tab 192 extending from an edge of the sleeve.FIG. 23 shows an exploded view of the transportation sleeve andcartridge assembly with an axis X-X' extending through theaforementioned components. Referring to the above figures, the sleevecan include a sleeve base 202 and a sleeve lid 208 configured to beoperably coupled to each other. The sleeve base can include an opening204 for receiving the cartridge assembly. The opening can be configuredto couple to the cartridge holder (e.g. proximal to the cartridge tab).The sleeve can include a dual support-release mechanism comprising (a) aretention element configured to engage with a corresponding matingfeature on the cartridge and secure the cartridge within the sleeve, and(b) a release element configured to cause the spring-clips on thecartridge holder to release and thereby decouple the cartridge from thecartridge holder. In some embodiments, the dual support-releasemechanism can be implemented using a plurality of posts 206 and 207.

FIG. 24A shows a side sectional view of the transportation sleeve withthe cartridge assembly inserted therein. FIG. 24B shows a side sectionalview with the cartridge holder removed, leaving the cartridge within thetransportation sleeve. As shown in the above figures, the cartridgeassembly is inserted into the opening 204 of the sleeve 200 by pushingthe cartridge tab 192 until a rear portion of the cartridge holder andthe seal/gasket 194 comes into contact with and seals the opening 204.The posts 206 can be configured to engage and release the spring clips196 on the cartridge holder when the cartridge assembly is properlyinserted into the sleeve. The release of the spring clips decouples thecartridge from the cartridge holder. The posts 207 can serve asstoppers, and come into contact with a portion of the cartridge adjacentto the cartridge port 184. As shown in FIG. 24B, the cartridge holdercan be subsequently removed from the sleeve, leaving the cartridge heldin place by posts 206 and 207 within the sleeve. As described above, thepost 206 and 207 can provide the dual support-release mechanism. Thedecoupling of the cartridge from the cartridge holder via the dualsupport-release mechanism can permit the cartridge holder to be removedfrom the opening of the sleeve while the cartridge is secured in placewithin the sleeve, without exposure of the strips to the ambientenvironment.

In some embodiments, additional treatment and/or stabilization of thesample on the matrices 186 can take place within the transportationsleeve following the release of the cartridge from the cartridge holder.In some embodiments, a desiccant can be provided within the sleeve fordrying the sample on the matrices. In some embodiments, the sleeve canbe placed in a carrier pouch 220 and shipped for further processing (seee.g., steps 13 and 14 of FIG. 25B).

FIGS. 25A and 25B illustrate exemplary procedures to collect and storeblood samples using any of the devices described herein (e.g. device100). Referring to FIG. 25A, the device can first be removed from itspackaging (step 1). A subject or another user (e.g. a healthcarepersonnel) can record the patient's information on a sleeve label (step2). An alcohol swab is then used to clean the skin on the patient'supper arm where the device will be applied (step 3). Next, an adhesiveliner is removed from the planar portion on the housing base of thedevice to reveal a hydrogel adhesive (step 4). Next, the device isplaced and adhered to the patient's skin with the hydrogel adhesive(step 5). The button labeled “1” on the device is pressed to activatethe vacuum to drawn the patient's skin into the recess (step 6). Thebutton labeled “2” on the device is next pressed to activate one or morepiercing elements to penetrate the patient's skin at the opening of therecess (step 7). Blood is absorbed by one or more matrices in thecartridge of the device. As blood is absorbed, the flow meter on thedevice can indicate the progress of the blood collection, and indicatewhen the matrices are full (step 8). Once the matrices are full, thedevice is removed (step 9). The cartridge is removed from the device(step 10) and inserted into a transportation sleeve (step 11). Thedevice is no longer needed and can be disposed appropriately in a sharpscontainer (step 12). The sleeve can be placed into a pouch (step 13)which is used to ship the sample to a lab for processing (step 14).

IV. Additional Embodiments

Provided herein are devices, methods, and kits for collecting blood froma subject. Devices, methods, and kits provided herein can permitapplication of a vacuum to skin of a subject, followed by piercing ofthe skin of the subject under vacuum (e.g., with one or more blades).Application of the vacuum can enhance blood flow to a region of skinunder vacuum and can increase the rate and volume of blood collection inthe device. The vacuum can be generated using a cupping action via,e.g., a rigid concave surface or flexible concave surface, e.g., aconcave cavity (see, e.g., FIGS. 31A-31D). A volume of a hemisphereformed by the concave surface can be equivalent to, or about half, orabout a quarter, of a volume of a vacuum chamber in the device. Theconcave cavity can comprise an opening with an inner diameter, and theconcave cavity can comprise a diameter at a base of the device.

Any of the devices provided herein can comprise one or more piercingelements, e.g., blades. The one or more piercing elements, e.g., blades,can be configured to pass through the opening of the device and piercethe skin of a subject. Each of one or more blades can comprise a lengthof about 1 mm to about 10 mm, or about 1 mm, 1.5 mm, 2 mm, 4 mm, 6 mm, 8mm, 10 mm, a width of about 0.01 to about 2 mm, or about 0.01 mm, 0.05mm, 0.1 mm, 0.5 mm, 1 mm, 2 mm, and a depth of about 1 to about 20 mm,or about 1, 5, 10, 15, or 20 mm. The devices can comprise one or morepiercing elements, e.g., at least 1, 2, 3, 4, 5, 6, or 7 piercingelements (e.g., lancets, needles, or blades).

A method for collecting blood from a subject is provided herein, themethod comprising applying a vacuum to skin of a subject using a device;after applying the vacuum, piercing the skin of the subject under whichthe vacuum is applied, wherein the device is used to pierce the skin ofthe subject, thereby generating an incision in the skin under which thevacuum is applied; and collecting the blood from the incision under thevacuum, wherein the collecting occurs in the device. The vacuum candeform skin, enhance perfusion and draw blood from the smaller incisionarea. The vacuum can be a global vacuum. A local vacuum can also beused, but the skin deformation and perfusion can be much less.

In some embodiments, the subject has diabetes. In some embodiments,collecting blood from a subject further comprises stabilizing acomponent or analytes of interest from the blood. In some embodiments,the analyte of interest is hemoglobin A1c (HbA1c).

The device can be configured with user friendly features. FIG. 31A, FIG.31B, FIG. 31C, and FIG. 31D illustrate features that can be integratedinto devices disclosed in the present application. Such features caninclude single or multiple (e.g., 2, 3, 4, 5) actuators or activators(e.g., which can include buttons) for device activation, with positionsthat can be readily activatable by the user given the shape of thedevice and location of the actuator. Actuators or activators can havedistinct shapes, sizes, and locations configured (e.g. positioned orstructured on the device) for ease of use (e.g. easy identification bythe user and well placed locations for simple activation). An example ofa device with actuators or activators for performing one or more userdirect actions is shown in FIG. 31A, wherein two buttons are shown eachwith an easily identified shape and comfortable to use location. Thecircular button shown in FIG. 31A can be used for activating a vacuumand the rectangular button can activate a piercing element (e.g.,lancet) for piercing the skin. In some cases, a single actuator oractivator can be used to activate a vacuum and a piercing element. Thedevice can comprise a lancet activation actuator configured to activatethe lancet upon actuation of the lancet activation actuator. The lancetactivation actuator can comprise a button.

Features, e.g., user friendly features, can comprise mechanisms forexpediting blood collection by enhancing a rate or means of collecting asample, thus reducing the time it takes to collect a sample. One suchfeature is illustrated in FIG. 31B, which depicts a device with askin-vacuum and lancing cavity for reducing the amount of time requiredto collect a sample. The skin-vacuum and lancing cavity can comprise aconcave cavity into which the skin of the subject can be drawn (e.g.,under negative pressure), and an opening comprising an inner openingthrough which a one or more piercing elements (e.g., lancets), e.g., 1,2, 3, 4, 5, 6, 7, 8, 9, or 10 piercing elements, can exit and pierceskin so that a blood sample can be drawn from the subject. In someembodiments the device can comprise a vacuum actuator (e.g., button) foractivating the vacuum.

FIG. 31C shows additional features. For example a device for collectinga blood sample can comprise a visual metering window that can allow auser to monitor sample collection and determine when the samplecollection is complete. When the sample collection is complete, a visualmetering window can be used to detect (e.g., visualize) a feature,colorimetric change, display of a symbol, masking of a symbol, or othermeans of indicating that collection is complete. Further user friendlyfeatures can comprise a removable cartridge (e.g., clip-in removablecartridge) for collecting and transporting a blood sample, as shown inFIG. 31D. A removable cartridge (e.g., clip-in removable cartridge) cancomprise a cartridge tab for releasing and removing the cartridge. Insome embodiments a removable cartridge (e.g., clip-in removablecartridge) can comprise a solid matrix for collecting, storing, and/orstabilizing a collected sample, and the removable cartridge canfacilitate easy transport (e.g. transport at room temperature), andtransport without the need for subsequent sample preparation orstabilization procedures.

FIG. 50A shows an additional embodiment of the visual metering windowand illustrates how blood absorption on the matrix strips can appear. Insome embodiments a wicking pad captures excess blood unable to beabsorbed by the matrix strips (FIG. 50B). Blood absorption on the matrixstrips is illustrated in FIG. 50C.

FIG. 32A, FIG. 32B, FIG. 32C, and FIG. 32D illustrate an integrateddevice with several of the user features described in FIG. 31A, FIG.31B, FIG. 31C, and FIG. 31D. FIG. 32A illustrates a front view of adevice with a dual button configuration. In some embodiments one buttoncan be responsible for activating a vacuum and a second button can beresponsible for activating a piercing (e.g., lancet piercing) mechanism;for example, the lower round button or vacuum button can be configuredto cause a vacuum (negative gauge pressure) to be applied to the skin,and the upper rectangular button or lancet button can be configured toactivate a vertical lancing mechanism to pierce the skin. In alternateembodiments buttons can be activated using a variety of methods; forexample the buttons can be activated separately, in a specific sequenceor order, or the two buttons can be combined into one button so thatonly a single button is needed to activate the collection mechanisms onthe device. Buttons can perform different functions, and have differentshapes, sizes, colors, or locations that support the function of eachbutton. FIG. 32B illustrates a side view of the device depicted in FIG.32A. FIG. 32B illustrates a device with a lancet housing, the lancethousing in this embodiment comprises a raised area for houses thelancing mechanism. Also depicted is a removable cartridge for storing asolid matrix, with a cartridge tab for removing the removable matrixcartridge. FIG. 32C depicts an alternate view of the device illustratedin FIGS. 32A and 32B. Illustrated features include the rear cartridgelid closure and cartridge tab, as well a visual metering widowconfigured to alert the user when the draw is complete. FIG. 32Dillustrates a side perspective view of the device illustrated in FIG.32A, FIG. 32B, and FIG. 32C.

FIG. 33A depicts the bottom view of a device for collecting a bloodsample, the depicted bottom region is the site of the device configuredfor making contact with the skin of the subject. As shown, the bottom ofthe device can comprise a concave cavity, for example a concavehemispherical cavity as shown here, although other shapes can also beused. The concave cavity in this embodiment forms a hemispherical cupdisposed within the bottom of the device. The cupped skin area can besubstantially larger than the lanced area. In some embodiments the ratioof the cupped skin to the lanced area can be greater than 20:1, greaterthan 30:1, greater than 40:1, greater than 50:1, greater than 60:1,greater than 70:1, greater than 80:1, greater than 90:1, or greater than100:1. In some embodiments the cupped area can be within 20% margin of500 mm2 and the lanced area can be within a 20% margin of 8 mm². Thelanced area can comprise a hole in the center of the concave cavity fromwhich lancets can protrude; this area can additionally act as a vacuumchannel and as part of the blood path to the deposition cartridge. Thelancets or other piercing element can be held in a cylinder shapedlancet actuator. The lancet actuator can have a diameter of 1-10 mm(e.g. 1, 2, 3, 4, 5, 6, 7, 9, 10 mm). The area of the lancet actuatorcan be between 5 and 100 mm² (e.g. 5, 10, 13.2, 15, 20, 40, 60, 80, 100mm²). The lancets or blades held by the lancet actuator can generate anincision area of between land 20 mm² (e.g. 1, 3, 5, 9, 11, 15, 17, 20mm²).

Any of the sample acquisition devices herein can also be referred to asthe “device,” The housing, outer housing, upper housing, lower housing,or lancet housing of the device can comprise acrylobutadiene styrene(ABS), polypropylene (PP), polystyrene (PS), polycarbon (PC),polysulfone (PS), polyphenyl sulfone (PPSU), polymethyl methacrylate(acrylic) (PMMA), polyethylene (PE), ultra high molecular weightpolyethylene (UHMWPE), lower density polyethylene (LPDE), polyamide(PA), liquid crystal polymer (LCP), polyaryl amide (PARA), polyphenylsufide (PPS), polyether etherketone (PEEK), polyvinyl chloride (PVC),polyethylene terephthalate (PET), polytetra flouroethylene (PTFE),polyaryletherketone (PAEK), polyphenyl sulfone (PPSU), or a combinationthereof. In some embodiments, the outer housing comprises polypropylene.

After the device is placed on the skin of the subject and the device isactivated, a vacuum or pressure differential can form between thesurface of the skin as well as components disposed within the device.Skin can be pulled into the cavity by the pressure differential and canbe constrained by the walls of the cavity. At some point after thevacuum is formed between the device and the skin, a piercing element(e.g., a lancet) can be activated to pierce the skin. As such, thevacuum “cupping” can be configured to enhance blood flow to the lancedarea and also aspirate blood from the opening collection site, throughthe device and into a collection cartridge.

A side view of the device depicted in FIG. 33A is illustrated in FIG.33B. In some embodiments the bottom of the device can comprise a curvedbase. Slight curvature at the base of the device can allow the device tobetter conform to the patient's anatomy (e.g., arm, e.g., upper arm) andcan guide orientation of the device. In some embodiments, the devicedescribed herein is used to draw blood from the arm. In someembodiments, the device is not used to draw blood from the fingertip. Insome embodiments, the device is not used to draw blood from a neonate.

Collection of the sample can comprise steps and components configuredfor piercing (e.g., lancing) the subject's skin and providing orcreating a vacuum to facilitate extraction of the sample. In someinstances a vacuum can be provided before lancing of the skin; in otherinstances the vacuum can be provided after lancing of the subject'sskin, and in still other instances the vacuum can be providedsimultaneously with lancing the subject's skin. FIG. 33A and FIG. 33Billustrate features of a device that can facilitate efficient bloodcollection using application of a vacuum to the skin of the subject. Thevacuum can operate as a means of deforming the skin, and this actioncoupled with lancing of the deformed skin can facilitate samplecollection. In further instances the device can be configured to performone or more additional processing steps (e.g. treatment, stabilization,and storage of the collected sample).

FIGS. 33A and 33B illustrates an embodiment of a device for collecting asample using global vacuum and local suction. Methods for using thedevice can comprise multiple steps. For example, a device as depicted inFIG. 33A and FIG. 33B can be placed on the arm of a subject using theorientation illustrated in FIG. 33C. The global vacuum cavity can beplaced in contact with the skin, and a seal can be created with anadhesive material or gasket material placed on the foot of the device(e.g. in curved surface of the device show in FIG. 33B). Vacuum can beapplied with the press of a button or other mechanism. Thereafter,lancing can be applied, for example utilizing a spring loaded plungingmechanism which cause two (can be more or fewer) lancets to penetratethe skin and retract. Lancing can be performed by a single blade ormultiple blades (e.g. two or more, three or more, four or more, five ormore, or ten or more blades). Blades can have various tip sized andshapes (e.g. slanted, triangular, circular, pointed, blunt, serrated).In instances where more than one blade is present, blades can beconfigured or arranged into patters with different shapes ororientations (e.g. ring, star, hash, square, rectangular etc.)

After sample is collected additional processing steps can be performedon the sample. Once blood is collected using a sample acquisitiondevice, the sample can be treated, stabilized and stored. In someembodiments collection devices, e.g. devices disclosed in the presentapplication, can be configured to collect, treat, and store the sample.Sample drawn by the device can be stored in liquid or solid form. Thesample can undergo optional treatment before being stored. Storage canoccur on the device, off the device, or in a removable container,vessel, compartment, or cartridge within the device.

A sample acquisition device can be configured to collect, treat,stabilize, and store a collected sample. Additional processing (e.g.treatment, stabilization, and storage) can comprise steps or methods anddevice components configured for concentrating the sample, adjusting ormetering the flow of the sample, exposing the sample to one or morereagents, and depositing the sample on a solid substrate or matrix.Methods for using a sample acquisition device can include steps toperform one or more of the following processes: collection, treatment,stabilization, and storage of the sample. Collection, treatment,stabilization, and storage can be performed within a single device.Treatment can comprise filtration of the sample to separate componentsor analytes of interest. In some embodiments, the collected sample canbe collected, treated, and stabilized prior to transfer to a removablecartridge for storage. In other embodiments, one or more stepscomprising collecting, treating, and stabilizing, can occur on aremovable cartridge.

In some embodiments, single action (e.g. activation using a button) canactivate alternate processing steps including sample treatment,stabilization, and storage. Additional processing steps can be performedon the device in response to single action, or in some instances two ormore user actions can be necessary to move the sample through one ormore different processes (e.g. collection, treatment, stabilization, andstorage). User actions can comprise pressing a single button, pressingmultiple buttons, pressing two or more buttons at the same time, andpressing two or more buttons in a prescribed sequence (e.g. based on aprescribed sequence to perform a set of treatment steps desired by theuser.)

Sample collected on a device can undergo a treatment step prior to beingdeposited on a solid substrate. A cartridge containing the two or moredeposition strips can be maintained in a near vertical orientation toreduce deposition speed and increase sample deposition consistency.Vacuum can be released by the user and device can be removed when avisual (or other) metering mark is observed. The sample cartridgecontaining the two or more solid matrix strips can be removed from thedevice.

In some embodiments, solid matrix strips can be sized to maximize bloodcollection volume while still fitting into commonly used containers(e.g. a 3 ml BD vacutainer, deep well plate or 2 ml Eppendorf tube).Solid matrix can be configured to meter out, collect and stabilize fixedvolumes of blood or plasma (e.g. greater than 25 uL, 50 uL, greater than75 uL, greater than 100 uL, greater than 125 uL, greater than 150 uL,greater than 175 uL, greater than 200 uL, or greater than 500 uL ofblood or plasma). A solid matrix can comprise cellulose based paper(e.g. Whatman™ 903 or 226 paper), paper treated with chemicals orreagents for stabilizing the sample or one or more components of thesample (e.g. RNA stabilization matrix or Protein Stabilization Matrix).In some embodiments, the solid matrix comprises a cellulose filterpaper. In some embodiments, any suitable commercially available filterpaper is used. Examples of commercially available filter paper include,but are not limited to, filter paper from Whatman®, such as 903 samplecollection cards and fast transit analysis (FTA®) card. In someembodiments, the solid matrix comprises a nitrocellulose filter paper.In some embodiments, the solid matrix does not comprise glass fiberfilter paper.

Sample acquisition devices (e.g. the devices depicted in FIGS. 31A-D,FIGS. 32A-D, and FIGS. 33A-C) can comprise a removable cartridge orenclosure for storing a liquid sample or solid matrix for removing thesample once it has been collected. FIG. 34A, FIG. 34B, FIG. 34C, andFIG. 34D illustrate steps for removing a removable cartridge from anexemplary devices configured with a removable cartridge (e.g. thedevices depicted in FIGS. 31A-D, FIGS. 32A-D, and FIGS. 33A-C). A devicecan come with a cartridge pre-loaded in the device, as shown in FIG.34A, or a device can come without the cartridge such that a cartridgecan be acquired separately and installed into the device by the userprior to sample collection. The device illustrated in FIG. 34A is shownwith the cartridge loaded in the device and with the cartridge tabprojecting from the back of the device. After a draw is complete thecartridge can be removed as shown. The cartridge can comprise one ormore solid matrix strips, or a vessel for storing liquid sample.Alternatively, the cartridge can be empty. In some cases, the cartridgecan include liquid handling reagents. In some embodiments, thecartridge/device interface can contain a seal (e.g. gasket or othertype) to maintain internal pressure during the draw period.

FIG. 34B illustrates the partially removed cartridge. Removal of thecartridge can be performed using the cartridge tab shown in FIG. 34A. InFIG. 34C, the cartridge depicted in FIG. 34B has been completely removedand is placed at the back of the collection device in an orientation bywhich it was removed. FIG. 34D illustrates the fully removed cartridgeplaced parallel with the collection device to illustrate the positioningof the cartridge within the device. Once removed, a cartridge can beplaced in a secondary vessel with desiccant to dry the sample. Ininstances where the cartridge comprises strips of solid matrix forstoring the sample, the strips can be removed with an extraction tool orother mechanism prior to analysis.

A cartridge, for example the cartridge illustrated in FIGS. 34A-D, cancomprise multiple components for facilitating accurate and precisesample collection. FIG. 35 illustrates a cross sectional and zoom-in ofa cartridge embodiment that can be used in any of the devices disclosedherein. In some instances a cartridge can comprise one or more solidmatrices for collecting a blood sample. In embodiments where two or moresolid matrices are included in the sample, the matrices can be stackedor arranged in ways that facilitate blood collection, distribution,precision and reproducible volumes of sample or analyte per surface areaof solid substrate. In instances where two or more solid matrices areinclude, the matrices can have different compositions or purposes; forexample one matrix can separate cells from a cell free component andcollect the cell free component on one matrix, and a second matrix orother matrices can collect raw unseparated sample.

An exemplary sample storage cartridge is depicted in FIG. 35. Thecartridge can comprises two pieces, a top piece and a bottom piece whichcan be merged to form internal chambers. Sample can move through theopening in the concave cavity of the device and into the cylinder shapedsample inlet into a tunnel inlet before entering a chamber. The chambercan comprise solid matrix strips for absorbing the sample and a spacer(e.g., plastic spacer) to separate the two solid matrix strips. Thespacer (e.g., plastic spacer) between the two strips can be adjustableand removable, depending on other relevant aspect (e.g. the needs andapplication of the sample being collected, stability of the analyte,rate of absorption requirements etc). The spacer (e.g., plastic spacer)can comprise a range of widths and coatings. Exemplary widths includewidths in the millimeter to centimeter range (e.g. greater than 2 mm,greater than 4 mm, greater than 6 mm, greater than 8 mm, greater than 10mm, greater than 0.2 cm, greater than 0.4 cm etc.). In furtherembodiments, the spacer (e.g., plastic spacer) can be coated withmaterials including hydrophobic coatings, hydrophilic coatings,antimicrobial coatings, coatings that bind to one or more components ofa sample, coatings for binding to or inhibiting enzymes that can degradeor otherwise impact the quality of one or more analytes on the sample.

As shown in FIG. 35, after moving thought the sample chamber, excesssample can move out of the storage cartridge through a wicking tail. Thewicking tail can be configured to absorb excess sample overflow. Thewicking tail can be configured (e.g. composition adjusted) so that thewicking tail can be used as a means to control the volume of the sampleabsorbed on the solid matrix strips. In further embodiments, the wickingtail can be used as or incorporated into an indicator or be visiblethrough a viewing window configured for informing a user that thecollection procedure is complete. The cartridges illustrated in FIG. 35depict sample stored on a solid matrix; however, this should not betaken to limit the devices disclosed herein—devices can comprisecartridges or means for collecting, treating, stabilizing and storingsample in either a liquid or a solid state.

FIG. 36A and FIG. 36B illustrate an exemplary device configured with asample storage cartridge similar to the cartridge illustrated in FIG.35. FIG. 36A shows a removable outer housing configured for applyingglobal vacuum to the sample collection site located on a subject's arm.In some embodiments the global vacuum can be applied through a concavecavity for deforming the skin prior to lancing. FIG. 36B illustratesexemplary local suction and blood collection components of the devicedepicted in FIGS. 36A and 36B. A depression is apparent on the arm ofthe subject, indicating that global suction was applied. Local suction,through a suction cup, is provided on the surface of the skin around thelocation where the skin of the subject was lanced. The sample is showingmoving from the lanced site into a cartridge comprising a saturatedmatrix and a wicking tail. The wicking tail can be used to absorb excesssample and standardize or meter the volume of blood deposited on thesaturated matrix.

In some embodiments, solid matrices, for example solid matrices includedin a cartridge, can be sized to maximize blood collection volume whilestill fitting into commonly used containers (e.g. a 3 ml BD vacutainer,deep well plate or 2 ml Eppendorf tube). The cartridge can include onesolid matrix, two solid matrices, three solid matrices, four solidmatrices, or more than four solid matrices. In some embodiments, thecartridge includes two solid matrices. Solid matrix can be configured tometer out, collect and stabilizes fixed volumes of blood or plasma (e.g.greater than 50 uL, greater than 75 uL, greater than 100 uL, greaterthan 125 uL, greater than 150 uL, greater than 175 uL, greater than 200uL, or greater than 500 uL of blood or plasma). In some embodiments, thecartridge comprises two solid matrices, wherein each solid matrixstabilizes 75 μL of blood for a total of 150 μL of blood. A solid matrixcan comprise cellulose based paper (e.g. Whatman™ 903 paper), papertreated with chemicals or reagents for stabilizing the sample or one ormore components of the sample (e.g. RNA stabilization matrix or ProteinStabilization Matrix).

Devices for collecting a blood sample can be modular, with two or morecompartments for performing specific actions or functions on the device.An exemplary modular device is depicted in FIG. 37A, FIG. 37B, FIG. 37C,and FIG. 37D. FIG. 37A illustrates the top view of a modular sampleacquisition device (e.g. similar to the devices depicted in FIGS. 31A-D,FIGS. 32A-D, and FIGS. 33A-C, and FIGS. 34A-D). Disposed within the topcover of the device illustrated in the FIG. 37A, is a lancet module anda lancet button for activating the lancet module. FIG. 37B illustratesthe vacuum chamber and cartridge chamber disposed within the lowerportion or “foot” of the device. This module comprises a pierceablevacuum chamber and a cartridge chamber, within the cartridge chamber isa cartridge. Projecting out of the backside of the device is a cartridgetab, which can be used to remove the cartridge as illustrated in FIGS.34A-D. FIG. 37C illustrates a cross section of the device. The crosssection displays the top cover and lancet module also shown in FIG. 37A,and in the bottom of the device the vacuum chamber/cartridge chambershown in FIG. 37B. Also shown in FIG. 37C is a side view of theremovable cartridge with the cartridge tabs, the cartridge is removedfrom the device and positioned to the side of the cartridge chamberwhere the cartridge can be inserted or from where the cartridge can beremoved. FIG. 37D illustrates a top view of the device in a top downview showing components present in FIG. 37B. FIG. 37D shows the vacuumbutton, with a sharp end for piercing the evacuated chamber, piercingthe evacuated chamber can form suction pulling the sample through theopening of the concave cavity, into the sample inlet of the cartridgeand onto the solid matrix strips in the cartridge.

FIGS. 38A-38F shows various views of an exemplary embodiment of a deviceconfigured for single activation piercing and collection of a bloodsample from a patient. As shown in FIG. 38A the device can comprise alow profile mold with a removable lancet safety sticker, and a buttonfor single activation of the device. FIG. 38B illustrates the internalworkings of the device in an exemplary starting position. In thestarting position, a moveable blade holder is held in a spring-loadedstate by a button hook that releases the blade holder when the buttondepressed. The device also comprises a path or track for the releasedblade holder to move along once the blade holder is released. Alsoillustrated in FIG. 38B is the sample collection site and the moveablecollection arm. FIG. 38C illustrates the internal workings of the deviceonce the button is depressed (1), and the blade holder is released (2).When the button is depressed the moveable blade holder is released, andmoves down the path or track. At this point in device activation, themoveable collection arm is still in the initial position, disposed abovethe sample collection site with sufficient space for the moveable bladeholder to move between the moveable blade holder and the samplecollection site. FIG. 38D illustrates the internal working of thedevice. Once released, the button actuated moveable blade holder rotatesthrough the device by moving along the path or track. At the end of thepath or track it actuates a latch, thereby releasing the bloodcollection arm. FIG. 38E shows a side view of the device, illustratingthe movable blade holder reaching the end of the path or track where theremovable blade holder releases a latch that activates the spring loadedblood collection arm resulting in release of the spring loadedcollection arm (3). The blood collection arm is released over the samplecollection site. Also depicted in FIG. 38E are the blades and anexemplary depth of the blades at a depth by which the blades areconfigured to project through the bottom of the device and into thesubjects skin. The depth of the blades is established by the shape andheight of the track or path on which the moveable blade holder travels.FIG. 38F illustrates the formation of a seal by the released bloodcollection arm over the sample collection site (4). The exemplary deviceillustrated in FIGS. 38A-38F comprises four steps for activation; firsta single button is depressed causing a blade holder to be released andthe blade holder moves down the depicted track or path. Along the path,the blades held by the blade holder pierce the skin, and at the end ofthe blade holder track or path the blade holder activates a latch thatreleases a spring loaded collection arm over the sample collection site.The collection arm forms a seal with the sample collection site, and thecollection arm can draw the blood from the subject. In some instances,the device illustrated in FIGS. 38A-38F can comprise an evacuatedchamber or onboard vacuum for creating suction.

An alternate embodiment of a low profile sample acquisition device isshown in FIGS. 39A-39E. A top view (FIG. 39A), bottom view (FIG. 39B),and side view (FIG. 39C) of an exemplary low profile sample acquisitiondevice, along with internal views of the device (FIG. 39D and FIG. 39E),illustrate the button, blade holder with two blades, collection arm,collection arm main spring and release spring, as well as the latch thatreleases the collection arm. In this embodiment (FIG. 39D and FIG. 39E),the button can be depressed by the user, causing the blade holder andinstalled blades to rotate, driven by the main spring, and during therotation pierce the subject's skin, at the end of the rotation the bladeholder can activate the collection arm latch that releases thecollection arm spring causing the collection arm to release bringing itin contact with the skin of the subject. The collection arm can createcontact with the skin, and can be configured to provide suction orvacuum to extract blood sample.

The devices illustrated in FIGS. 38A-38F and FIGS. 39A-39E, and anydevices disclosed in the present application, can comprise a single ormultiple blades for piercing a subjects skin; for example one or more,two or more, three or more, four or more, five or more, or ten or moreblades. Blades can be configured in different shapes or orientations,for example a ring shape, a star shape, a hash shape, square shapes,rectangular shapes, etc.

The devices illustrated in FIGS. 38A-38F and FIGS. 39A-39E, and anydevices disclosed in the present application, can be configured tocollect, treat, and store the sample. The sample drawn by the device canbe stored in liquid or solid form. The sample can undergo optionaltreatment before being stored. Storage can occur on the device, off thedevice, or in a removable container, vessel, compartment, or cartridgewithin the device.

The devices illustrated in FIGS. 38A-38F and FIGS. 39A-39E, and anydevices disclosed in the present application can be configured tocollect, treat, stabilize, and store a collected sample. A device can beconfigured to perform one or more of the following processes:collection, treatment, stabilization, and storage of the sample.Collection, treatment, stabilization, and storage can be performedwithin a single device. Treatment can comprise filtration of the sampleto separate components or analytes of interest. Treatment can alsocomprise exposure to buffers or reagents for stabilizing the sample. Insome embodiments the device can be configured to concentrate one or morecomponents of the sample.

In some instances, one or more of the processes (e.g. collection,treatment, stabilization, and storage of the sample) can be performed onthe device in response to singe activation of the device by the user. Inother instances two or more user actions can need to be performed tomove the sample through one or more different processes (e.g.collection, treatment, stabilization, and storage). User actions cancomprise pressing a single button, pressing multiple buttons, pressingtwo or more buttons at the same time, and pressing two or more buttonsin a prescribed sequence (e.g. based on a prescribed sequence to performa set of treatment steps desired by the user.)

Collection of the sample can comprise steps and components configuredfor lancing the subject's skin and providing or creating a vacuum toextract the sample. In some instances a vacuum can be provided beforelancing of the skin, in other instances the vacuum can be provided afterlancing of the subject's skin, in further instances the vacuum can beprovided simultaneously with lancing the subject's skin.

Treatment of the device can comprise concentrating the sample, adjustingor metering the flow of the sample, exposing the sample to one or morereagents, and depositing the sample on a solid substrate or matrix.Embodiments the device can comprise a removable cartridge or enclosurefor storing a liquid sample or solid matrix for removing the sample onceit has been collected. A solid matrix can comprise cellulose based paper(e.g. Whatman™ 903 paper), paper treated with chemicals or reagents forstabilizing the sample or one or more components of the sample (e.g. RNAstabilization matrix or Protein Stabilization Matrix).

Devices for collecting a blood sample from a subject can also rely on avertically oriented device, as shown in FIGS. 40A-40D, FIGS. 41A-41B,and FIGS. 42A-42C.

FIG. 40A illustrates an exemplary embodiment of a sample acquisitiondevice with a vertical cutting modality. The device can comprise asyringe with syringe plunger, connected to a housing comprising aplunger and a blade. The device can comprise a housing within which aplunger and blade or disposed. The housing can be oriented towards theskin of the subject with the syringe and syringe plunger oriented awayfrom the subject. FIG. 40B shows the same device positioned on its sideto illustrate the cup shaped shield with slits for the blades. FIG. 40Cillustrates a side view of the housing portion of the device in thestarting position. The view illustrates the presence of a chamber sealedbetween the housing and a plunder disposed within the housing. The bladeis held in a spring-loaded state by a ridge disposed within the housing.On the bottom of the device, a cup-shaped shield with slits allowsblades to move through the cup-shaped shield to pierce the skin of thesubject and, through micro-channels cut into the cup-shaped shield,direct blood flow to the center of the cup. FIG. 40D is a side view ofthe device with a view of the housing and the plunder disposed within.Also visible on the bottom of the device is the cup-shaped shield withblades projecting through the slits of the cup-shaped shield, showinghow cutting of the skin of the subject is performed.

Methods for using the device illustrated in FIGS. 40A-40D, areillustrated in FIG. 41A and FIG. 41B. As shown in FIG. 41A, a lancetsafety ring is then removed from the device (1). At this point, thedevice is still in the locked position with the blade resting on a ridgewithin the device (See FIG. 41B). Then a user pushes down on the outerring (2), depressing an internal spring and releasing the blade (3). Theblade then rotates (4a-4d) cutting the skin of the user and exposingblood that moves into the cup-shaped shield. Finally, the user pulls onthe syringe plunger (5) to create negative pressure and draw the samplethrough the micro channels and slits in the bottom of the cup-shapedshield, and into the syringe.

FIG. 42A, FIG. 42B, and FIG. 42C illustrate a device with a verticalrotational cutter similar to those illustrated in FIGS. 40A-40D, andFIGS. 41A-41B, however a wound spring mechanism is used to control ablade holder and thus drive rotation of the blade in the device. FIG.42A illustrates the blade and spring, with the blade in the lockedposition—resting on a features within the housing, with the springloaded. A force is applied to the top of the device to depress thespring (1a), and the blade is free to rotate (1b). As shown in FIG. 42B,the blade rotates through the path (2a-2d) during which it cuts the skinof the subject, until it reaches an unloaded state. The cut skin of thesubject releases blood sample which moves through the shield whichdirects blood follow towards the center, as shown in FIG. 42C (sideview). A possible flap “valve” can be included that covers the bladeaccess slits and form a seal to close the suction. Finally, as shown inFIG. 42C, the syringe can be retracted and the sample can be draw into asample storage compartment disposed within the device.

Sample acquisition devices (e.g. devices illustrated in FIGS. 40A-40D,FIGS. 41A-41B, and FIGS. 42A-42C, can comprise a single or multipleblades for piercing a subjects skin; for example one or more, two ormore, three or more, four or more, five or more, or ten or more blades.Blades can be configured in different shapes or orientations, forexample a ring shape, a star shape, a hash shape, square shapes,rectangular shapes, etc.

Sample acquisition devices (e.g. devices illustrated in FIGS. 40A-40D,FIGS. 41A-41B, and FIGS. 42A-42C, can be configured to collect, treat,and store the sample. The sample drawn by the device can be stored inliquid or solid form. The sample can undergo optional treatment beforebeing stored. Storage can occur on the device, off the device, or in aremovable container, vessel, compartment, or cartridge within thedevice.

Sample acquisition devices (e.g. devices illustrated in FIGS. 40A-40D,FIGS. 41A-41B, and FIGS. 42A-42C, can be configured to collect, treat,stabilize, and store a collected sample. A device can be configured toperform one or more of the following processes: collection, treatment,stabilization, and storage of the sample. Collection, treatment,stabilization, and storage can be performed within a single device.Treatment can comprise filtration of the sample to separate componentsor analytes of interest. In some instances one or more of the processes(e.g. collection, treatment, stabilization, and storage of the sample)can be performed on the device in response to singe activation of thedevice by the user. In other instances two or more user actions can needto be performed to move the sample through one or more differentprocesses (e.g. collection, treatment, stabilization, and storage). Useractions can comprise pressing a single button, pressing multiplebuttons, pressing two or more buttons at the same time, and pressing twoor more buttons in a prescribed sequence (e.g. based on a prescribedsequence to perform a set of treatment steps desired by the user.)

Collection of the sample can comprise steps and components configuredfor lancing the subject's skin and providing or creating a vacuum orsuction to extract the sample. In some instances a vacuum or suction canbe provided before lancing of the skin, in other instances the vacuum orsuction can be provided after lancing of the subject's skin, in furtherinstances the vacuum can be provided simultaneously with lancing thesubject's skin.

Treatment of the device can comprise concentrating the sample, adjustingor metering the flow of the sample, exposing the sample to one or morereagents, and depositing the sample on a solid substrate or matrix.Embodiments the device can comprise a removable cartridge or enclosurefor storing a liquid sample or solid matrix for removing the sample onceit has been collected. A solid matrix can comprise cellulose based paper(e.g. Whatman™ 903 paper), paper treated with chemicals or reagents forstabilizing the sample or one or more components of the sample (e.g. RNAstabilization matrix or Protein Stabilization Matrix).

FIG. 43B illustrates a device configured for applying global vacuum andlocal suction to collect a sample. Lancet blades can be used to piercethe skin of a subject prior to applying the device to collect thesample. Lancets can comprise high flow or low flow. After lancing, adevice for applying global vacuum and local suction is applied to thelocation of the cut. The device, as shown in FIG. 43B, can comprise twonested components, an outer element for applying global vacuum to deformthe skin and an inner element for providing local suction. Connected tothe inner element is a tube with a luer adaptor at the end of it,suction is provided through the luer adaptor, enabling sample to bedrawn into the collection tube. The suction provided through the lueradaptor is used to both deform the skin and to extract the sample.

The method and device for collecting a blood sample, as illustrated inFIG. 43B is configured to collect a targeted volume of blood in under 5minutes. Examples of blood volumes and corresponding collection timesfor seven samples are presented in Table 1. The average blood volumedrawn was 245 uL+/−12.2 uL in an average of 1.9 minutes+/−0.8 minutes.The average rate for blood collection was 127 uL per minutes. Bloodsamples collected methods and devices comprising global vacuum and localsuction can cover the range of greater than 50 uL per minute, greaterthan 75 uL per minute, greater than 100 uL per minute, greater than 125uL per minute, greater than 150 uL per minute, greater than 175 uL perminute and greater than 200 uL per minute. Examples of the pressuregenerate by the global vacuum can include greater than 5 inHg, greaterthan 8 inHg, greater than 10 inHg, greater than 12 inHb, and anypressures or ranges of pressures sufficient to pull skin into chamber ofthe outer element and create overall vacuum on skin in the tube.

Mechanisms that incorporate global vacuum and local suction can increasethe rate of sample collection over methods that do not have globalvacuum and local suction. Table 1 below illustrates draw times forglobal vacuum and local suction device illustrated in FIG. 43B. Globalvacuum and local suction can comprise any method or device configuredfor, under negative pressure, sucking or deforming skin into a largercavity and drawing blood sample out of the surface of the sample. Inmechanisms that rely on global vacuum and local suction there can be twoor more contacts; for example the outer element (e.g. the bell shapedcup) and the inner element (e.g. inner local suction cup). These nestedelements can be configured such that the ratio of the effected surfaceareas (e.g. ratio generated by the surface area of the global vacuumarea divided by the local suction area) are present at a particularratio. The ratio can be configured to deform the skin and then disruptthe site above the incision to facilitate extraction of the sample.

Draw times for Global Vacuum Local Suction Blood Collection MethodGlobal Vacuum with 25 mm Cup and Suction Cup + Measured Tubing (2×Becton Dickinson (BD) High Flow lancets) Blood Volumes Draw Times Draw(uL) (min) 1 232 2.2 2 236 3.5 3 246 1.7 4 245 1.8 5 262 1.8 6 236 1.0 7261 1.5 Ave 245 1.9 Std Dev:   12.2 0.8 Ave Draw Rate: 127   

The devices illustrated in FIGS. 43A and 43B, and any sample acquisitiondevices disclosed in the present application, can comprise a single ormultiple blades for piercing a subjects skin; for example one or more,two or more, three or more, four or more, five or more, or ten or moreblades. Blades can be configured in different shapes or orientations,for example a ring shape, a star shape, a hash shape, square shapes,rectangular shapes, etc.

The devices illustrated in FIGS. 43A and 43B, and any sample acquisitiondevices disclosed in the present application, can be configured tocollect, treat, and store the sample. The sample drawn by the device canbe stored in liquid or solid form. The sample can undergo optionaltreatment before being stored. Storage can occur on the device, off thedevice, or in a removable container, vessel, compartment, or cartridgewithin the device.

The devices illustrated in FIGS. 43A and 43B, and any sample acquisitiondevices disclosed in the present application can be configured tocollect, treat, stabilize, and store a collected sample. A device can beconfigured to perform one or more of the following processes:collection, treatment, stabilization, and storage of the sample.Collection, treatment, stabilization, and storage can be performedwithin a single device. Treatment can comprise filtration of the sampleto separate components or analytes of interest.

In some instances one or more of the processes (e.g. collection,treatment, stabilization, and storage of the sample) can be performed onthe device in response to singe activation of the device by the user. Inother instances two or more user actions can need to be performed tomove the sample through one or more different processes (e.g.collection, treatment, stabilization, and storage). User actions cancomprise pressing a single button, pressing multiple buttons, pressingtwo or more buttons at the same time, and pressing two or more buttonsin a prescribed sequence (e.g. based on a prescribed sequence to performa set of treatment steps desired by the user.)

The device can be adhered to the skin of a patient with an adhesive. Insome embodiments, any suitable adhesive is used. The adhesive can be ahydrogel, an acrylic, a polyurethane gel, a hydrocolloid, or a siliconegel.

The adhesive can be a hydrogel. In some embodiments, the hydrogelcomprises a synthetic polymer, a natural polymer, a derivative thereof,or a combination thereof. Examples of synthetic polymers include, butare not limited to poly(acrylic acid), poly(vinyl alcohol) (PVA),poly(vinyl pyrrolidone) (PVP), poly (ethylene glycol) (PEG), andpolyacrylamide. Examples of natural polymers include, but are notlimited to alginate, cellulose, chitin, chitosan, dextran, hyaluronicacid, pectin, starch, xanthan gum, collagen, silk, keratin, elastin,resilin, gelatin, and agar. The hydrogel can comprise a derivatizedpolyacrylamide polymer.

In some embodiments, the adhesive comes attached to the device. Thedevice can comprise a protective film or backing covering the adhesiveon the base of the device, wherein prior to use the protective film isremoved. In another embodiment, an adhesive in the form of a gel, ahydrogel, a paste, or a cream is applied to skin of the subject or thebase of the device prior in order to adhere the skin to the device. Theadhesive can be in contact with the patient for less than about 10minutes. In some embodiments, the adhesive is a pressure-sensitiveadhesive. In some embodiments, the adhesive is hypoallergenic.

Collection of the sample can comprise steps and components configuredfor lancing the subject's skin and providing or creating a vacuum toextract the sample. In some instances a vacuum can be provided beforelancing of the skin, in other instances the vacuum can be provided afterlancing of the subject's skin, in further instances the vacuum can beprovided simultaneously with lancing the subject's skin.

Treatment of the device can comprise concentrating the sample, adjustingor metering the flow of the sample, exposing the sample to one or morereagents, and depositing the sample on a solid substrate or matrix.Embodiments the device can comprise a removable cartridge or enclosurefor storing a liquid sample or solid matrix for removing the sample onceit has been collected. A solid matrix can comprise cellulose based paper(e.g. Whatman™ 903 paper), paper treated with chemicals or reagents forstabilizing the sample or one or more components of the sample (e.g. RNAstabilization matrix or Protein Stabilization Matrix).

FIGS. 44A and 44B illustrate a device configured for horizontal cutting,with simultaneous seal formation. The device can comprise a squareshaped outer casing. A blade holder can be installed on a track, and theblade can be arranged to move on a semi-circular track. When theactuator is depressed, the blade moves along the semi-circular track,cutting an elastomeric material (e.g. polyurethane) and creating a sealbetween an adhesive (e.g. hydrogel) circle or donut shaped materialdisposed from the base of the device. In this embodiment the activationof the actuator triggers the blade which cuts the elastomeric materialforming a seal, while simultaneously lancing the subject's skin. FIG.44A shows the blade before it is actuated, and FIG. 44B shows the bladeafter it has cut the elastomeric material and formed a seal with thesubject's skin.

The devices illustrated in FIGS. 44A-44B, and any sample acquisitiondevices disclosed in the present application, can comprise a single ormultiple blades for piercing a subjects skin; for example one or more,two or more, three or more, four or more, five or more, or ten or moreblades. Blades can be configured in different shapes or orientations,for example a ring shape, a star shape, a hash shape, square shapes,rectangular shapes, etc.

The devices illustrated in FIGS. 44A-44B, and any sample acquisitiondevices disclosed in the present application, can be configured tocollect, treat, and store the sample. The sample drawn by the device canbe stored in liquid or solid form. The sample can undergo optionaltreatment before being stored. Storage can occur on the device, off thedevice, or in a removable container, vessel, compartment, or cartridgewithin the device.

The devices illustrated in FIGS. 44A-44B, and any sample acquisitiondevices disclosed in the present application can be configured tocollect, treat, stabilize, and store a collected sample. A device can beconfigured to perform one or more of the following processes:collection, treatment, stabilization, and storage of the sample.Collection, treatment, stabilization, and storage can be performedwithin a single device. Treatment can comprise filtration of the sampleto separate components or analytes of interest.

In some instances, one or more of the processes (e.g. collection,treatment, stabilization, and storage of the sample) can be performed onthe device in response to singe activation of the device by the user. Inother instances two or more user actions can need to be performed tomove the sample through one or more different processes (e.g.collection, treatment, stabilization, and storage). User actions cancomprise pressing a single button, pressing multiple buttons, pressingtwo or more buttons at the same time, and pressing two or more buttonsin a prescribed sequence (e.g. based on a prescribed sequence to performa set of treatment steps desired by the user.)

Collection of the sample can comprise steps and components configuredfor lancing the subject's skin and providing or creating a vacuum toextract the sample. In some instances a vacuum can be provided beforelancing of the skin, in other instances the vacuum can be provided afterlancing of the subject's skin, in further instances the vacuum can beprovided simultaneously with lancing the subject's skin.

Treatment of the device can comprise concentrating the sample, adjustingor metering the flow of the sample, exposing the sample to one or morereagents, and depositing the sample on a solid substrate or matrix.Embodiments the device can comprise a removable cartridge or enclosurefor storing a liquid sample or solid matrix for removing the sample onceit has been collected. A solid matrix can comprise cellulose based paper(e.g. Whatman™ 903 paper), paper treated with chemicals or reagents forstabilizing the sample or one or more components of the sample (e.g. RNAor DNA).

Any of the embodiments disclosed in the present application can comprisea vacuum chamber. Vacuum chambers can vary in size, shape, pressure, andcan have structural variations as well as a variety of mechanisms forgenerating the vacuum. A vacuum chamber can come pre-charged using anonboard evacuated chamber (e.g. a chamber installed on the device usinga membrane that when penetrated generates negative pressure incontiguous enclosures), or generated through user action by way of asyringe or other means of generating negative pressure. The vacuumchamber (e.g. evacuated chamber) can seal on one end with foil orelastomer (e.g. polyisoprene) on the other end, such that piercing thefoil or septum allows the vacuum to generate within the device. Vacuumchamber sizes can vary, for example the vacuum chamber can be greaterthan 2 mL, greater than 4 mL, greater than 6 mL, greater than 8 mL, orgreater than 10 mL in volume. One embodiment of a vacuum chamber isillustrated in FIGS. 45A-45C. FIGS. 45A and 45B illustrates a side viewof a vacuum chamber that could be used in the disclosed devices. Thevacuum chamber can comprise a Polyisoprene septum with a needleconnected to a small diameter tube to apply the vacuum. The chamber canalso comprise, on the opposite side, a luer adaptor so that a syringecan be connected through a check valve to create the vacuum. The vacuumchamber can comprise an opening, a vacuum chamber cap, and one or morescrew holes with screws for holding the cap in place. FIG. 45C shows aside view of a vacuum chamber, as well as a zoom-in view of the grovesthat hold the septum in place and illustration of the type of needlesthat can be used with the vacuum chamber.

Once a device lances the skin of a subject and the blood sample is drawninto the device, the sample can be optionally treated then stored on asample collection matrix. The storage and sample treatment methods cancomprise treating the sample to fix the volume, uniformity, orconcentration of the sample deposited on sample collection matrix.Methods and devices for collecting and storing the sample on the matrixcan comprise a cartridge or compartment that can be removed from thedevice. An exemplary cartridge or compartment for depositing and storingthe collected sample is illustrated in FIGS. 46A-46C.

FIG. 46A, FIG. 46B, and FIG. 46C illustrate a sample collection matrixfor collecting and storing sample on a stabilization matrix. As shown inFIG. 46A, the sample collection matrix can comprise an inlet where theblood sample is drawn into a channel within the device that allows bloodto flow along the bottom of the solid matrix. A vacuum draw is presenton the other side of the device to draw the sample into the solidmatrix. The sample collection housing can comprise a upper housing and alower housing (as shown in FIGS. 46B and 46C) with the matrix andchannel moving sample within the housing, disposed between the upper andlower housing. A tongue and groove feature can create a seal between theupper and lower housing.

FIG. 47 illustrates components of a device or kit for collecting asample from a subject. The kit can comprise a sample collection device,a removable cartridge transport sleeve with desiccant (with or without abarcode or label), a removable blood storage matrix cartridge, bloodstorage matrix strips, and a cartridge transport bag.

FIG. 48 illustrates methods by which a user can acquire a sample usingthe kit. The kit can be obtained and the user can insert the cartridgeinto the device. Steps executed by the user can comprise using thedevice to collect a sample, remove the cartridge once sample collectionis complete, place the removable cartridge into the transportationsleeve with desiccant, and place it in the cartridge transport bag.Multiple samples can be taken by the user, and then the user can shipthe sample(s) to a facility for analysis.

FIG. 49 illustrates exemplary method steps that a laboratory can performupon receipt of a shipping container containing the sample(s). Thesample pouch can be removed from the shipping container, the samplecartridge can be removed from the sample pouch, and the pull tab canthen be removed from the cartridge. Matrix #1 can be removed from thecartridge and placed in an extraction tube, then matrix #2 can beremoved from the cartridge and placed in an extraction tube. Theextraction tube matrix #2 is placed in can be a different extractiontube from the extraction tube matrix #1 is placed in. The extractiontube matrix #2 is placed in can be the same extraction tube from theextraction tube matrix #1 is placed in. The extraction tube can be amicrofuge tube. From there any number of tests or analyses can beperformed on the sample.

The devices, systems, and methods disclosed herein can stabilize sampleon a matrix (e.g. blood storage matrix, sample collection matrix,matrix, sample stabilization matrix, stabilization matrix (e.g. RNAStabilization Matrix, Protein Stabilization Matrix), solid matrix, solidsubstrate, solid support matrix, or solid support). The matrix can beintegrated into the device, or external to the device. In someembodiments the matrix can be incorporated into a cartridge for removal(e.g. after sample collection). In some embodiments the matrix canmatrix comprise a planar dimensional that is at least 176 mm². A matrixcan be prepared according to the methods of U.S. Pat. Nos. 9,040,675,9,040,679, 9,044,738, or U.S. Pat. No. 9,480,966 of which are all hereinincorporated by reference in their entirety.

In some embodiments, a system, a method, or a device can comprise a highsurface area matrix that selectively stabilizes nucleic acids orproteins. In some instances the matrix can be configured to comprise aplanar sheet with total dimensional area (length multiplied by width)greater than 176 mm².

The matrix can be configured to selectively stabilize sample preparationreagents comprising protein and/or nucleic acids. The matrix can beconfigured to stabilize protein and nucleic acids can comprise anoligosaccharide (e.g. a trisaccharide) under a substantially dry state.The oligosaccharide or trisaccharide can be selected from a groupcomprising: melezitose, raffinose, maltotriulose, isomaltotriose,nigerotriose, maltotriose, ketose, cyclodextrin, trehalose orcombinations thereof. In some embodiments the matrix can comprisemelezitose. In further embodiments the melezitose can be under asubstantially dry state. In some embodiments, melezitose under asubstantially dry state can have less than 2% of water content. In thematrix, the concentration of the melezitose can be in range of about 10%to about 30% weight percent by mass (e.g. calculates as the mass of thesolute divided by the mass of the solution where the solution comprisesboth the solute and the solvent together. The concentration ofmelezitose can be 15% weight percent by mass. The melezitose can beimpregnated in the matrix. In some embodiments, the impregnatedmelezitose concentration in the matrix results from immersing the matrixin a melezitose solution comprising between about 10 to about 30%. Insome other embodiments, 15% melezitose is impregnated into the matrix ina dried state. The matrix can be passively coated or covalently-modifiedwith melezitose. In other embodiments the melezitose can be applied tothe surface of the matrix (e.g. with dipping, spraying, brushing etc.).In some other embodiments, the matrix can be coated with a 15% solutionof melezitose. In some embodiments the matrix can matrix comprise aplanar dimensional with a surface area that is at least 176 mm². In someembodiments the melezitose can be present at greater than 0.01 ng/mm²,greater than 0.05 ng/mm², greater than 0.1 ng/mm², greater than 0.5ng/mm², greater than 1 ng/mm², greater than 5 ng/mm², greater than 0.01μg/mm², greater than 0.05 μg/mm², greater than 0.1 μg/mm², greater than1 μg/mm², greater than 5 μg/mm², greater than 0.01 mg/mm², greater than0.05 mg/mm², greater than 0.1 mg/mm², greater than 1 mg/mm², greaterthan 5 mg/mm², greater than 10 mg/mm², greater than 50 mg/mm², greaterthan 1 μg/mm², greater than 5 μg/mm², or greater than 10 μg/mm². Thematrix can comprise additional components to stabilize protein and/ornucleic acids, including various stabilization molecules. A non-limitingexample of a stabilization molecule is validamycin. In some embodimentsthe matrix can comprise 31-ETF (e.g. cellulose based matrix) andmelezitose.

The matrix can comprise a buffer reagent. A buffer reagent can beimpregnated into the matrix. Buffers can stabilize sample preparationreagents and/or various sample components. The matrix can furtherinclude at least one buffer disposed on or impregnated within thematrix, wherein the matrix can be substantially dry with a water contentof less than 2%. The buffer can be an acid-titrated buffer reagent thatgenerates a pH in a range from about 3 to about 6, or about 2 to about7. The matrix can contain any one of the following:2-Amino-2-hydroxymethyl-propane-1,3-diol (Tris), 2-(N-morpholino)ethanesulfonic acid (MES), 3-(N-morpholino) propanesulfonic acid (MOPS),citrate buffers, 4-(2-hydroxyethyl)-1-piperazineethanesulfonic acid(HEPES), phosphate buffers or combinations thereof, orTris-Hydrochloride (TrisHCl). The matrix can be configured to yield asolution upon rehydration comprising about 20 to about 70 mM Tris-HCland about 5 to about 30 mM MgCl₂. The amount of various dehydratedbuffer reagents impregnated into a matrix can be configured forstabilizing sample preparation reagent(s).

The matrix can comprise a reagent or compound that minimizes nucleaseactivity, e.g., a nuclease inhibitor. Examples of nuclease inhibitorsinclude RNase inhibitor, compounds able to alter pH such as mineralacids or bases such as HCl, NaOH, HNO₃, KOH, H₂SO₄, or combinationsthereof; denaturants including urea, guanidine hydrochloride,guanidinium thiocyanate, a one metal thiocyanate salt that is notguanidinium thiocyanate (GuSCN) beta-mercaptoethanol, dithiothreitol;inorganic salts including lithium bromide, potassium thiocyanate, sodiumiodide, or detergents including sodium dodecyl sulfate (SDS).

The matrix can comprise a reagent or compound that minimizes or inhibitsprotease activity, e.g., a protease inhibitor. A protease inhibitor canbe synthetic or naturally-occurring (e.g., a naturally-occurring peptideor protein). Examples of protease inhibitors include aprotinin,bestatin, chymostatin, leupeptin, alpha-2-macroglobulin, pepstatin,phenylmethanesulfonyl fluoride, N-ethylmaleimide,ethylenediaminetetraacetid acid, antithrombin, or combinations thereof.In one example, protease inhibitors enhance the stability of theproteins by inhibiting proteases or peptidases in a sample.

The matrix can comprise one or more free radical scavengers. The matrixcan comprise a UV protectant or a free-radical trap. Exemplary UVprotectants include hydroquinone monomethyl ether (MEHQ), hydroquinone(HQ), toluhydroquinone (THQ), and ascorbic acid. In certain aspects, thefree-radical trap can be MEHQ. The matrix can also comprise oxygenscavengers, e.g. ferrous carbonate and metal halides. Other oxygenscavengers can include ascorbate, sodium hydrogen carbonate and citrus.

The matrix can comprise a cell lysis reagent. Cell lysis reagents caninclude guanidinium thiocyanate, guanidinium hydrochloride, sodiumthiocyanate, potassium thiocyanate, arginine, sodium dodecyl sulfate(SDS), urea or a combination thereof. Cell lysis reagents can includedetergents, wherein exemplary detergents can be categorized as ionicdetergents, non-ionic detergents, or zwitterionic detergents. The ionicdetergents can comprise anionic detergent such as, sodiumdodecylsulphate (SDS) or cationic detergent, such as ethyl trimethylammonium bromide. Examples of non-ionic detergent for cell lysis includeTritonX-100, NP-40, Brij 35, Tween 20, Octyl glucoside, Octylthioglucoside or digitonin. Some zwitterionic detergents can comprise3-[(3-Cholamidopropyl)dimethylammonio]-1-propanesulfonate (CHAPS) and3-[(3-Cholamidopropyl)dimethylammonio]-2-hydroxy-1-propanesulfonate(CHAPSO). The cell lysis reagent can comprise a thiocyanate salt. One ormore embodiments of the solid support matrix comprises a thiocyanatesalt impregnated in a dry state. Exemplary thiocyanate salts include,but are not limited to, guanidinium thiocyanate, sodium thiocyanate,potassium thiocyanate or combinations thereof. In some otherembodiments, the cell lysis reagent is selected from guanidiniumthiocyanate, sodium thiocyanate, sodium dodecyl sulfate (SDS) orcombinations thereof.

A solid support matrix can comprise a reducing agent. Reducing agentscan include dithiothreitol (DTT), 2-mercaptoethanol (2-ME),tris(2-carboxyethyl)phosphine (TCEP) and combinations thereof. Reducingagents can further comprise oxygen scavengers. Oxygen scavengers orreducing agents can comprise ferrous carbonate and metal halides. Asolid support matrix can comprise a chelating agent. Chelating agentscan include ethylenediaminetetraacetic acid (EDTA), citric acid,ethylene glycol tetraacetic acid (EGTA), or combinations thereof. Thesolid support matrix can be configured to provide an acidic pH uponhydration and/or preserve nucleic acids in a substantially dry state atambient temperature. The solid support matrix can be configured toprovide a pH between about 2 and about 7 upon hydration. The solidmatrix can be configured to provide a pH between about 3 and about 6upon hydration.

In some embodiments, a sample can be filtered or separated before beingdeposited on a matrix. Liquid sample can collect or pool into acollection chamber, after the collection chamber or in lieu of acollection chamber the sample can optionally be absorbed through one ormore particles, materials, structures or filters with optimized porosityand absorptivity for drawing the sample into the device. Materials fordrawing the sample into the devices herein can consist of any absorptiveor adsorptive surfaces, or materials with modified surfaces; optionalmaterials including but not limited to paper-based media, gels, beads,membranes, matrices including polymer based matrices, or any combinationthereof.

In some embodiments, the device or cartridge can comprise a sampleseparation unit comprising one or more substrates, membranes, or filtersfor separating sample components. The sample separation unit can beintegrated within the sample stabilization component, or it can beattached to or separate from the sample stabilization component. In someembodiments, sample separation can occur as an intermediate step betweensample acquisition and transfer of sample to the matrix. In someinstances sample separation and stabilization can occur in one stepwithout the need for user intervention. Sample separation can furtheroccur sequentially or simultaneously with sample stabilization.

In some embodiments, sample acquisition and stabilization can requireuser action to proceed between one or more phases of the samplecollection, optional separation, and stabilization process. A device canrequire user action to activate sample acquisition, and move samplebetween separation, stabilization, and storage. Alternatively, useraction can be required to initiate sample acquisition as well as one ormore additional steps of the sample collection, separation orstabilization process. User action can include any number of actions,including pushing a button, tapping, shaking, rupture of internal parts,turning or rotating components of the device, forcing sample through oneor more chambers and any number of other mechanisms. Movement throughthe phases can occur in tandem with sample collection, or can occurafter sample collection. Anytime during or prior to the processingphases the entire sample or components of the sample can be exposed toany number of techniques or treatment strategies for pre-treatment ofcells of biological components of the sample; potential treatmentincludes but is not limited to treatment with reagents, detergents,evaporative techniques, mechanical stress or any combination thereof.

In some embodiments, the devices described herein are configured to drawcapillary blood.

In some embodiments, the devices disclosed herein are designed to beused once and then discarded. Resterilization or reuse can compromisethe structural integrity of the device or increase the risk ofcontamination or infection leading to device failure, cross-infection,or patient injury, illness, or death.

FIG. 53 and FIG. 56 illustrate exemplary procedures to collect and storeblood using a device described herein.

Disclosed herein, in certain embodiments, are kits for use with one ormethods described herein. A kit can include the device for blood samplecollection described herein. The kit can comprise a sample pouch ortransportation sleeve, wherein the pouch or sleeve is used to store acartridge comprising at least one solid matrix strip. A desiccant can beadded to the pouch or sleeve. In some embodiments, the desiccant is asilica gel desiccant. The kit can further comprise a sample returnenvelope, a bandage, an alcohol prep pad, a gauze pad, or a combinationthereof.

A kit can include labels listing contents and/or instructions for use,and package inserts with instructions for use. A set of instructions canbe included.

In one embodiment, a label is on or associated with the pouch or sleeve.In one embodiment, a label is on a pouch or sleeve when letters, numbersor other characters forming the label are attached, molded or etchedinto the pouch or sleeve itself, a label can be associated with a pouchor sleeve when it is present within a receptacle or carrier that alsoholds the pouch or sleeve, e.g., as a package insert. The label canindicate directions for use of the contents, such as in the methodsdescribed herein.

The devices, methods, systems and kits disclosed herein can comprise oneor more sample separation units. Sample separation units can be used,e.g., to separate plasma from blood, cells from a water sample, or cellsfrom cell free components. The solid matrix can be used to storecirculating or cell-free nucleic acids (e.g. DNA or RNA) separated froma sample, e.g., a blood sample, after filtration. The circulating DNAcan be tumor circulating DNA. For blood samples one or more componentscan be used to separate plasma or specific cells from other componentsof a blood sample. Alternatively, devices, methods and systems canselectively separate any number of sample components including cells,plasma, platelets, specific cell types, DNA, RNA, protein, inorganicmaterials, drugs, or any other components.

Non-limiting embodiments of the sample stabilization unit can employsample separation components to separate other non-plasma components aswell. Sample separation components can be connected to the sampleacquisition component e.g., through channels, including microchannels,wicking of absorbent materials or other means that allow sample to flowthrough the device. The systems and methods for separating the sampleare exemplary and non-limiting.

There are many methods for performing separation, some of which usesize, deformability, shape or any combination thereof. Separation canoccur through one or more membranes, chambers, filters, polymers, orother materials. Membranes, substrates, filters and other components ofthe device can be chemically treated to selectively stabilizecomponents, facilitate flow of sample, dry the sample, or anycombination thereof. Alternative separation mechanisms can includeliquid-liquid extraction, solid-liquid extraction, and selectiveprecipitation of target or non-target elements, charge separation,binding affinity, or any combination thereof. Separation phase can becomprised of one or more steps, with each step relying on differentmechanisms to separate the sample. One such mechanism can utilize size,shape or deformation to separate larger components from smaller ones.Cell separation can occur through a sorter that can, for example, relyon one or more filters or other size exclusion methods to separatecomponents of the sample. Separation can also be conducted throughselective binding wherein specific components are separated by bindingevents while the unbound elutant moves into or through alternatechambers.

In some devices, systems, methods, or kits, a single membrane,substrate, or filter can be used for separation and collection of one ormore sample components from the bulk sample. Single membrane, substrate,or filter methods can comprise a device wherein samples can be appliedto one end of the membrane, substrate, or filter and as the sample flowsthrough a first component of the sample, for example cells, can beseparated from a second component of the sample, for example plasma,based on the size of the membrane, substrate, or filter pores. Afteroperation of the device the membrane, substrate, or filter containingthe first component of the sample, cells in this example, can be severedfrom the portion containing the second component of the sample, plasmain this example, necessitating an additional step of severing themembranes, substrates, or filters. In another method, two separatemembranes, substrates, or filters can be used for the separation andcollection sample components; specifically, a first membrane, substrate,or filter for the separation of one component, for example blood cells,and a second membrane, substrate, or filter for collection of othercomponents, for example plasma. These membranes, substrates, or filterscan be arranged such that a distal end of the first membrane, substrate,or filter contacts a proximal end of the second membrane to facilitatethe separation of a large component, for example cells, via the firstmembrane, substrate, or filter and the collection of a second smallercomponent, for example plasma, via the second membrane, substrate, orfilter.

Generally, a sample can contain or is suspected of containing one ormore analytes. The term “analyte” as used herein can refer to anysubstance that can be analyzed using the assays or immunoassay devices.As an example, an immunoassay device can be configured to detect thepresence of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or more analytes in a sample.Non-limiting examples of analytes can include proteins, haptens,immunoglobulins, hormones, polynucleotides, steroids, drugs, infectiousdisease agents (e.g., of bacterial or viral origin), drugs of abuse,environmental agents, biological markers, and the like.

As used in the specification and claims, the singular form “a”, “an” and“the” include plural references unless the context clearly dictatesotherwise. For example, the term “a cell” includes a plurality of cells,including mixtures thereof.

As used herein, the term “about” a number refers to that number plus orminus 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, of that number.

While preferred embodiments of the present invention have been shown anddescribed herein, it will be obvious to those skilled in the art thatsuch embodiments are provided by way of example only. Numerousvariations, changes, and substitutions will now occur to those skilledin the art without departing from the invention. It should be understoodthat various alternatives to the embodiments of the invention describedherein can be employed in practicing the invention. It is intended thatthe following claims define the scope of the invention and that methodsand structures within the scope of these claims and their equivalents becovered thereby.

What is claimed is:
 1. A carrier for storing a blood sample duringtransportation, the carrier comprising: a cartridge assembly comprisinga cartridge and a cartridge holder releasably coupled to the cartridge,wherein the cartridge comprises one or more porous matrices on which theblood sample is collected; a chamber having an opening configured toreceive the cartridge assembly; and a release mechanism configured torelease the cartridge from the cartridge holder to provide a releasedcartridge; wherein the chamber is configured to store the releasedcartridge in a secured position.
 2. The carrier of claim 1, wherein theblood sample is in a substantially dried state.
 3. The carrier of claim1, wherein the blood sample is in a liquid state.
 4. The carrier ofclaim 1, wherein the cartridge holder is configured to releasably coupleto the carrier.
 5. The carrier of claim 4, wherein the cartridge ispartially released from the cartridge holder when the cartridge holderis coupled to the carrier.
 6. The carrier of claim 4, wherein thecartridge is fully released from the cartridge holder when the cartridgeholder is decoupled from the carrier.
 7. The carrier of claim 4, whereinthe one or more porous matrices are removable from the opening of thedumber when the cartridge holder is decoupled from the carrier.
 8. Thecarrier of claim 1, wherein the cartridge assembly further comprises agasket configured to close the opening and seal the chamber when thecartridge holder is coupled to the carrier.
 9. The carrier of claim 8,further comprising a desiccant in the chamber.
 10. The carrier of claim9, wherein the desiccant comprises silica gel.
 11. The carrier of claim9, wherein the desiccant and the sealing of the chamber collectively aidin improving a stability of one or more components of the blood samplewhen the blood sample is being stored in the chamber.
 12. The carrier ofclaim 1, further comprising: a retention mechanism configured to engagewith at least one mating feature on the cartridge to secure thecartridge within the chamber.
 13. The carrier of claim 12, wherein theretention mechanism and the release mechanism collectively provide adual support-release mechanism.
 14. The carrier of claim 13, wherein thedual support-release mechanism permits the cartridge holder to beremoved from the carrier while the cartridge is secured in place withinthe chamber.
 15. The carrier of claim 12, wherein the cartridge holderis releasably coupled to the cartridge via spring clips, and the releasemechanism is configured to cause the spring clips on the cartridgeholder to partially release the cartridge from the cartridge holder. 16.The carrier of claim 15, wherein the release mechanism comprises a firstset of posts that pushes apart the spring clips to partially release thecartridge when the cartridge assembly is coupled to the carrier.
 17. Thecarrier of claim 16, wherein the retention mechanism comprises the firstset of posts and a second set of posts, wherein the first and secondsets of posts contact different portions of the cartridge to constrainthe cartridge in the secured position.
 18. The carrier of claim 17,wherein at least two of the different portions of the cartridge arenon-coplanar with each other.
 19. The carrier of claim 17, wherein atleast two of the different portions of the cartridge are coplanar witheach other.
 20. The carrier of claim 17, wherein at least two of thedifferent portions of the cartridge are substantially parallel with eachother.
 21. The carrier of claim 17, wherein the second set of posts isconfigured to limit a travel distance of the cartridge into the chamber.22. The carrier of claim 17, wherein the first set of posts is incontact with laterally opposite side portions of the cartridge.
 23. Thecarrier of claim 22, wherein the at least one mating feature is locatedon the laterally opposite side portions of the cartridge.
 24. Thecarrier of claim 17, wherein the second set of posts is in contact witha distal portion of the cartridge.
 25. The carrier of claim 17, whereinthe cartridge comprises a fluid access port, and wherein the fluidaccess port is disposed between the second set of posts when thereleased cartridge is stored in the secured position within the chamber.26. The carrier of claim 1, wherein the carrier is sized and shaped toaccommodate user or patient identity (ID) labels.
 27. The carrier ofclaim 1, further comprising: a peelable foil for sealing the opening ofthe chamber prior to coupling the cartridge assembly to the carrier. 28.The carrier of claim 27, wherein the peelable foil is configured toprotect the chamber of the carrier from moisture and contamination priorto use of the carrier for storing and transporting the blood sample.